Genetic and Biochemical characterization of OXA-519, a novel OXA-48-like β-lactamase.
Genetic and Biochemical characterization of OXA-519, a novel OXA-48-like β-lactamase. Antimicrob Agents Chemother. 2018 Jun 04;: Authors: Dabos L, Bogaerts P, Bonnin RA, Zavala A, Sacré P, Iorga BI, Huang DT, Glupczynski Y, Naas T Abstract A multidrug-resistant K. pneumoniae 1210 isolate with reduced carbapenem susceptibility revealed the presence of a novel plasmid-encoded blaOXA-48-like gene, named blaOXA-519. The 60.7-kb plasmid (pOXA-519) was similar to the IncL-OXA-48 prototypical plasmid except for a ca. 2-kb deletion due to an IS1R insertion. OXA-519 differed from OXA-48 by a Val120...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Dabos L, Bogaerts P, Bonnin RA, Zavala A, Sacré P, Iorga BI, Huang DT, Glupczynski Y, Naas T Tags: Antimicrob Agents Chemother Source Type: research

Proposing Kluyvera georgiana as the origin of the plasmid-mediated resistance gene fosA4.
Abstract A putative fosA gene in Kluyvera georgiana 14751 showed 99% nucleotide identity with plasmid-encoded fosA4 Due to a single-nucleotide insertion translating to a truncated protein, K. georgiana 14751 fosA does not confer fosfomycin resistance. Nonetheless, analysis of another genome deposit (K. ascorbata WCH1410) that could be recategorized as K. georgiana after phylogenetic analysis, revealed a fosA 100% identical to the plasmid-borne fosA4 Collectively, we suggest that Kluyvera georgiana represents the most probable origin of fosA4. PMID: 29866858 [PubMed - as supplied by publisher] (Source: Antimic...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Rodriguez MM, Ghiglione B, Power P, Naas T, Gutkind G Tags: Antimicrob Agents Chemother Source Type: research

Pharmacokinetics of praziquantel in Schistosoma mansoni and Schistosoma haematobium infected school- and preschool- aged children.
The objective of this study was to establish and compare pharmacokinetic parameters of praziquantel in schistosomiasis infected preschool- and school-aged children.Two pharmacokinetic trials in school- and preschool-aged children infected with S. mansoni or S. haematobium, were conducted in Côte d'Ivoire. Dried blood spot samples were taken from 492 children at ten time points following a single oral dose of 20, 40 or 60 mg/kg of praziquantel and analysed using liquid chromatography mass spectrometry. Non-compartmental analysis (NCA) was performed to obtain pharmacokinetic parameters of R- and S-praziquantel (R- and ...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Kovač J, Meister I, Neodo A, Panic G, Coulibaly JT, Falcoz C, Keiser J Tags: Antimicrob Agents Chemother Source Type: research

Viability Screen of LOPAC1280 Reveals Phosphorylation Inhibitor Auranofin as Potent Inhibitor of Blastocystis ST1, ST4 and ST7 Isolates.
In this study, LOPAC1280 was screened and drugs that can decrease the viability of three Blastocystis isolates in cultures were identified. Using apoptosis assay and imaging flow cytometry, phenotypic changes in Blastocystis cells after treatment were also analyzed to obtain insights into the possible mechanism of action of these drugs. Three drugs - diphenyleneiodonium chloride, auranofin and BIX 01294 trihydrochloride hydrate, were effective against all three isolates tested. Repurposing of these drugs for Blastocystis treatment could be a way of combatting metronidazole resistance relatively quickly and at a lower cost....
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Yason JA, Koh KARP, Tan KSW Tags: Antimicrob Agents Chemother Source Type: research

Model system identifies kinetic driver of Hsp90 inhibitor activity against African trypanosomes and Plasmodium falciparum.
Abstract Hsp90 inhibitors, well-studied in the laboratory and clinic for antitumor indications, have promising activity against protozoan pathogens, including Trypanosoma brucei that causes African sleeping sickness, and malaria parasite Plasmodium falciparum To progress these experimental drugs toward clinical use we adapted an in vitro dynamic hollow-fiber system and deployed artificial pharmacokinetics to discover the driver of their activity: either concentration or time. Compounds from three major classes of Hsp90 inhibitors in development were evaluated against trypanosomes. In all circumstances tested Hsp90...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Meyer KJ, Caton E, Shapiro TA Tags: Antimicrob Agents Chemother Source Type: research

In Vitro Activity of Plazomicin against Gram-Negative and Gram-Positive Isolates Collected from United States Hospitals and Comparative Activity of Aminoglycosides against Carbapenem-Resistant Enterobacteriaceae and Isolates Carrying Carbapenemase Genes.
Abstract Plazomicin and comparators agents were tested using the CLSI reference broth microdilution method against 4,825 clinical isolates collected during 2014 and 2015 in 70 United States hospitals as part of the ALERT (Antimicrobial Longitudinal Evaluation and Resistance Trends) program. Plazomicin (MIC50/90, 0.5/2 μg/ml) inhibited 99.2% of 4,362 Enterobacteriaceae at ≤4 μg/ml. Amikacin, gentamicin, and tobramycin inhibited 98.9%, 90.3%, and 90.3% of these isolates, respectively, applying CLSI breakpoints. The activity of plazomicin was similar among Enterobacteriaceae species with MIC50 values ranging...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Castanheira M, Davis AP, Mendes RE, Serio AW, Krause KM, Flamm RK Tags: Antimicrob Agents Chemother Source Type: research

Diversity of carbapenemase-producing Escherichia coli isolates, France 2012-2013.
Abstract With the dissemination of carbapenemase-producing Enterobacteriaceae (CPE) worldwide, carbapenem-hydrolyzing enzymes are increasingly reported among Escherichia coli, the first hospital and community-acquired opportunistic pathogen. Here, we have performed an epidemiological survey of carbapenemase-producing E. coli (CP-Ec) isolates received at the French National Reference Centre (F-NRC) in 2012 and 2013. Antimicrobial susceptibilities for last resort antibiotics and antimicrobial compounds commonly used to treat urinary tract infections were determined by broth microdilution. Clonal relationship was ass...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Gauthier L, Dortet L, Cotellon G, Creton E, Cuzon G, Ponties V, Bonnin RA, Naas T Tags: Antimicrob Agents Chemother Source Type: research

Linezolid Kills Acid Phase and Non-replicative Persister Phase Mycobacterium tuberculosis in a Hollow Fiber Infection Model.
Abstract The therapy of Mycobacterium tuberculosis (MTB) infection is long and arduous. It has been hypothesized that the therapy duration is driven primarily by populations of organisms in different metabolic states that replicate slowly or not at all (Acid-phase and NRP-phase organisms). Linezolid is an oxazolidinone antimicrobial with substantial activity against Log-phase MTB. Here, we examined organisms in Acid-phase growth and Non-Replicative Persister phenotype growth and determined the effect of differing clinically-relevant exposures to linezolid in a Hollow Fiber Infection Model (HFIM). The endpoints mea...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Drusano GL, Myrick J, Maynard M, Nole J, Duncanson B, Brown D, Schmidt S, Neely M, Scanga CA, Peloquin C, Louie A Tags: Antimicrob Agents Chemother Source Type: research

Activities of oxadiazole antibacterials against Staphylococcus aureus and other Gram-positive bacteria.
Abstract The activities of four oxadiazoles were investigated with 210 methicillin-resistant Staphylococcus aureus (MRSA) strains. MIC50 and MIC90 values of 1-2 and 4 μg/ml, respectively, were observed. We also evaluated the activity of oxadiazole ND-421 against other staphylococci and enterococci and in the presence of oxacillin for selected MRSA. The MIC for ND-421 is lowered several fold in combination with oxacillin, as they synergize. The MIC90 of ND-421 against vancomycin-resistant enterococci (VRE) is ≤1 μg/ml. PMID: 29866865 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Ceballos S, Kim C, Ding D, Mobashery S, Chang M, Torres C Tags: Antimicrob Agents Chemother Source Type: research

In Vivo Efficacy of Plazomicin Alone or in Combination with Meropenem or Tigecycline against Enterobacteriaceae Isolates Exhibiting Various Resistance Mechanisms in an Immunocompetent Murine Septicemia Model.
The objective of this study was to assess the efficacy of plazomicin exposure, alone and in combination with meropenem or tigecycline, against Enterobacteriaceae in the immunocompetent murine septicemia model.Methods: ICR mice were inoculated intraperitoneally with bacterial suspensions. Eight Enterobacteriaceae isolates with wide ranges of plazomicin, meropenem and tigecycline MICs were utilized. Treatment mice were administered plazomicin, meropenem or tigecycline human-equivalent doses alone or in combinations of plazomicin/meropenem and plazomicin/tigecycline. Treatments were initiated 1h post-infection and continued f...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Abdelraouf K, Kim A, Krause KM, Nicolau DP Tags: Antimicrob Agents Chemother Source Type: research

Few conserved amino acids in the small multidrug resistance transporter EmrE influence drug polyselectivity.
This study reveals that few conserved residues are essential for drug polyselectivity and indicates that aromatic QCC selection involves a greater portion of conserved residues compared to other QCCs.Importance EmrE is an archetypical member of the small multidrug resistance efflux pump family and its members are frequently identified from mobile genetic elements and multidrug resistant plasmids. This study examines conserved residues in EmrE and their MIC to various quaternary ammonium compounds which may shed light on the importance of conserved residues in other EmrE orthologues. In this study, few conserved EmrE residu...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Saleh M, Bay DC, Turner RJ Tags: Antimicrob Agents Chemother Source Type: research

Artemisone and artemiside - potent pan-reactive antimalarial agents that also synergize redox imbalance in P. falciparum transmissible gametocyte stages.
Abstract The emergence of resistance towards artemisinin combination therapies (ACTs) by the malaria parasite Plasmodium falciparum has the potential to severely compromise malaria control. Therefore, development of new artemisinins in combination with new drugs that impart activities towards both intraerythrocytic proliferative asexual and transmissible gametocyte stages, in particular those of resistant parasites, are urgently required. We define artemisinins as oxidant drugs through their ability to oxidize reduced flavin cofactors of flavin disulfide reductases critical for maintaining redox-homeostasis in the...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Coertzen D, Reader J, van der Watt M, Nondaba SH, Gibhard L, Wiesner L, Smith P, D'Alessandro S, Taramelli D, Ning Wong H, du Preez JL, Wu RWK, Birkholtz LM, Haynes RK Tags: Antimicrob Agents Chemother Source Type: research

In vitro and intracellular activity of imipenem combined to rifabutin and avibactam against Mycobacterium abscessus.
Abstract Repurposing drugs may be useful as an add-on in the treatment of Mycobacterium abscessus pulmonary infections, which are particularly difficult to cure. M. abscessus naturally produces a β-lactamase, BlaMab, which is inhibited by avibactam. The recommended regimens include imipenem, which is hydrolyzed by BlaMab and used without any β-lactamase inhibitor. Here, we determine whether the addition of rifabutin improves the activity of imipenem alone or in combination with avibactam against M. abscessus CIP104536. Rifabutin at 16 μg/ml was only bacteriostatic (MIC = 4 μg/ml) and was moderately...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Le Run E, Arthur M, Mainardi JL Tags: Antimicrob Agents Chemother Source Type: research

In Vitro and In Vivo activity of a novel catheter lock solution against bacterial and fungal biofilms.
This report evaluates a new commercially developed antimicrobial catheter lock solution (ACL) containing trimethoprim (5 mg/ml) and ethanol (25%) and calcium Ethylenediaminetetraacetic acid (CA-EDTA) 3% for activity against bacterial and fungal biofilms using in vitro and in vivo (rabbit) catheter biofilm models. Biofilms were formed with bacterial (seven different species including vancomycin-resistant enterococcus, VRE) or fungal (C. albicans) species on catheter materials. Biofilm formation was evaluated by quantitative culture (colony forming units, CFUs) and scanning electron microscopy (SEM). Treatment with ACL inhib...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Chandra J, Long L, Isham N, Mukherjee PK, DiSciullo G, Appelt K, Ghannoum MA Tags: Antimicrob Agents Chemother Source Type: research

PET-PCR for Detection of Plasmodium falciparum Plasmepsin 2 Gene copy number.
Abstract Piperaquine is an important partner drug used in artemisinin-based combination therapies (ACTs). An increase in the plasmepsin 2 and 3 gene copy number has been associated with decreased susceptibility of Plasmodium falciparum to piperaquine in Cambodia. Here, we developed a photo- induced electron transfer real-time PCR (PET-PCR) assay to quantify the copy number of plasmepsin 2 (PfPM2) that can be used in endemic countries to enhance molecular surveillance. PMID: 29866871 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Santos Souza S, L'Episcopia M, Severini C, Udhayakumar V, Lucchi NW Tags: Antimicrob Agents Chemother Source Type: research

Primary fungal prophylaxis in hematological malignancy: A network meta-analysis of randomized controlled trials.
Abstract Several new anti-fungal agents have become available for primary fungal prophylaxis of neutropenia fever in haematological malignancy patients. Our aim was to synthesize all evidence on efficacy and enable an integrated comparison of all current treatments.We performed a systematic literature review to identify all publicly available evidence from randomized controlled trials (RCT). We searched Embase, PubMed, the Cochrane Central Register of Controlled Clinical Trials, and the website www.ClinicalTrials.gov In total, 54 RCTs were identified, including 13 treatment options. The evidence was synthesised us...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Lee CH, Lin C, Ho CL, Lin JC Tags: Antimicrob Agents Chemother Source Type: research

Efficacy of Meglumine Antimoniate under Low Polymerization State Orally Administrated in Murine Model of Visceral Leishmaniasis.
ute;zard F Abstract Progress towards the improvement of meglumine antimoniate (MA) commercially known as Glucantime®, a highly effective but also toxic antileishmanial drug, has been hindered by the lack of knowledge and control on its chemical composition. Here, MA was manipulated chemically with the aim of achieving an orally effective drug. MA compounds were synthesized from either antimony pentachloride (MA-SbCl5) or potassium hexahydroxyantimonate (MA-KSb(OH)6) and prepared under low polymerization state. Those were compared to Glucantime® regarding chemical composition, permeation properties across c...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Kato KC, de Morais-Teixeira E, Islam A, Leite MF, Demicheli C, de Castro WV, Corrêa-Junior JD, Rabello A, Frézard F Tags: Antimicrob Agents Chemother Source Type: research

Effect of Linezolid plus Bedaquiline against Mycobacterium tuberculosis in Log-Phase, Acid-Phase and Non-Replicating-Persister (NRP)-Phase in an In vitro Assay.
Abstract Tuberculosis is the ninth-leading cause of death worldwide. Treatment success is approximately 80% for susceptible strains and decreases to 30% for extensively resistant strains. Shortening therapy duration for Mycobacterium tuberculosis (Mtb) is a major goal, which can be attained with the use of combination therapy. However, the identification of the most promising combination is a challenge given the quantity of older and newer agents available. Our objective was to identify promising 2-drug combinations using an in vitro strategy to ultimately be tested in an in vitro Hollow Fiber Infection Model (HFI...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: de Miranda Silva C, Hajihosseini A, Myrick J, Nole J, Louie A, Schmidt S, Drusano GL Tags: Antimicrob Agents Chemother Source Type: research

Non-proteinogenic Amino Acid Containing Nucleotide Prodrug to Improve Oral Delivery of a Hepatitis C Virus Treatment.
Abstract Delivery of pharmacologically active nucleoside triphosphate analogs to sites of viral infection is challenging. In prior work we identified a 2'-C-methyl-1'-cyano-7-deaza-adenosine C-nucleotide analog with desirable selectivity and potency for the treatment of HCV infection. However, the prodrug selected for clinical development, GS-6620, required a high dose for meaningful efficacy and had unacceptable variability due to poor oral absorption as a result of suboptimal solubility, intestinal metabolism and efflux transport. While obtaining clinical proof of concept for the nucleotide analog, a more effect...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Feng JY, Wang T, Park Y, Babusis D, Birkus G, Xu Y, Voitenleitner C, Fenaux M, Yang H, Eng S, Tirunagari N, Kirschberg T, Cho A, Ray AS Tags: Antimicrob Agents Chemother Source Type: research

Evaluation of the Bactericidal Activity of Plazomicin and Comparators against Multidrug-resistant Enterobacteriaceae.
Abstract The next-generation aminoglycoside plazomicin, in development for infections due to multi-drug resistant (MDR) Enterobacteriaceae, was evaluated alongside comparators for bactericidal activity in minimum bactericidal concentration (MBC) and time-kill (TK) assays against MDR Enterobacteriaceae isolates with characterized aminoglycoside and β-lactam resistance mechanisms. Overall, plazomicin and colistin were the most potent, with plazomicin demonstrating an MBC50/90 of 0.5/4 μg/mL and sustained 3-log10 kill against MDR Escherichia coli, Klebsiella pneumoniae and Enterobacter spp. PMID: 2986687...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Thwaites M, Hall D, Shinabarger D, Serio AW, Krause KM, Marra A, Pillar C Tags: Antimicrob Agents Chemother Source Type: research

Pharmacodynamic and immunomodulatory effects of micafungin on host responses against biofilms of Candida parapsilosis in comparison to those of Candida albicans.
In conclusion, MFG may condition THP-1 cells towards an inflammatory response through TLR2/TLR4 recruitment. Inflammatory signals observed with C. albicans biofilms, are considerably reduced upon exposure of THP-1 cells to C. parapsilosis biofilms possibly enhancing fungal survival and increasing biofilm pathogenicity. PMID: 29866877 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Simitsopoulou M, Chlichlia K, Kyrpitzi D, Walsh TJ, Roilides E Tags: Antimicrob Agents Chemother Source Type: research

In vivo Efficacy of Relebactam (MK-7655) in Combination with Imipenem/Cilastatin in Murine Infection Models.
Abstract The World Health Organization has identified antimicrobial resistance as a global public health threat as the prevalence and spread of antibiotic resistance among bacterial pathogens worldwide are staggering. Carbapenems, such as imipenem and meropenem have been used to treat multidrug-resistant bacteria; however, since the development of resistance to carbapenems, β-lactam antibiotics in combination with β-lactamase inhibitors (BLI) has been one of the most successful strategies to enhance the activity of β-lactam antibiotics. Relebactam (REL) is a new BLI which has been found to inhibit C...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Powles MA, Galgoci A, Misura A, Colwell L, Dingley KH, Tang W, Wu J, Blizzard T, Motyl M, Young K Tags: Antimicrob Agents Chemother Source Type: research

Pentamidine for Prophylaxis against Pneumocystis jirovecii Pneumonia in Pediatric Oncology Patients Receiving Immunosuppressive Chemotherapy.
Abstract BACKGROUND: Pneumocystis jirovecii pneumonia is a life-threatening opportunistic infection in children receiving immunosuppressive chemotherapy. Without prophylaxis, up to 25% of pediatric oncology patients receiving chemotherapy will develop Pneumocystis jirovecii pneumonia. Trimethoprim-sulfamethoxazole is the preferred agent for prophylaxis against Pneumocystis jirovecii pneumonia. Pentamidine may be an acceptable alternative for pediatric patients unable to tolerate trimethoprim-sulfamethoxazole. METHODS: A retrospective review was conducted of pediatric oncology patients who received ≥ 1 dose...
Source: Antimicrobial Agents and Chemotherapy - June 4, 2018 Category: Microbiology Authors: Quinn M, Fannin JT, Sciasci J, Bragg A, Campbell PK, Carias D, Crews KR, Gregornik D, Jeha S, Maron G, Pauley JL, Swanson HD, Wolf J, Greene W Tags: Antimicrob Agents Chemother Source Type: research

Should We Accept Colistin-Induced Nephrotoxicity To Ensure Attainment of a Therapeutic Steady State in Those with Good Renal Function?
PMID: 29802204 [PubMed - in process] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - June 1, 2018 Category: Microbiology Authors: Plant AJ, Auckland C Tags: Antimicrob Agents Chemother Source Type: research

Antibacterial spectrum of a tetrazole-based reversible inhibitor of serine β-lactamases.
Antibacterial spectrum of a tetrazole-based reversible inhibitor of serine β-lactamases. Antimicrob Agents Chemother. 2018 May 29;: Authors: Pemberton OA, Zhang X, Nichols DA, DeFrees K, Jaishankar P, Bonnet R, Adams J, Shaw LN, Renslo AR, Chen Y Abstract CTX-M is the most prevalent family of extended-spectrum β-lactamases. We recently developed a tetrazole-derived non-covalent inhibitor of CTX-M-9. Here, we present biochemical and microbiological activity of this inhibitor across a representative panel of serine β-lactamases and Gram-negative bacteria. The compound displayed significan...
Source: Antimicrobial Agents and Chemotherapy - May 29, 2018 Category: Microbiology Authors: Pemberton OA, Zhang X, Nichols DA, DeFrees K, Jaishankar P, Bonnet R, Adams J, Shaw LN, Renslo AR, Chen Y Tags: Antimicrob Agents Chemother Source Type: research

Nephrotoxicity Associated with Intravenous Polymyxin B Once versus Twice Daily Dosing Regimen.
Abstract Nephrotoxicity is a known adverse effect of polymyxin B (PMB). Animal data suggests that once daily dosing may reduce the rate and delay the onset of acute kidney injury (AKI).In a multicenter, retrospective study, we evaluated adult patients with a creatinine clearance (CrCl) ≥30 mL/min who received ≥48h of PMB therapy. The primary endpoint was the difference in rate of AKI comparing once and twice daily PMB dosing. Secondary endpoints included time to AKI and recovery of renal function.Of 273 eligible patients, 100 from each group were matched based on propensity scores. In the matched groups, nep...
Source: Antimicrobial Agents and Chemotherapy - May 29, 2018 Category: Microbiology Authors: Okoduwa A, Ahmed N, Guo Y, Scipione MR, Papadopoulos J, Eiras DP, Dubrovskaya Y Tags: Antimicrob Agents Chemother Source Type: research

Fragments of the non-lytic proline-rich antimicrobial peptide Bac5 kill E. coli cells by inhibiting protein synthesis.
Wilson DN Abstract Unlike most antimicrobial peptides (AMPs), the main mode of action of the subclass of proline-rich antimicrobial peptides (PrAMPs) is not based on disruption of the bacterial membrane. Instead, PrAMPs exploit the inner membrane transporters SbmA and YjiL/MdtM to pass through the bacterial membrane and enter the cytosol of specific Gram-negative bacteria, where they exert an inhibitory effect on protein synthesis. Despite sharing a high proline and arginine content with other characterized PrAMPs, the PrAMP Bac5 has a low sequence identity with them. Here we investigated the mode of action of thr...
Source: Antimicrobial Agents and Chemotherapy - May 29, 2018 Category: Microbiology Authors: Mardirossian M, Barrière Q, Timchenko T, Müller C, Pacor S, Mergaert P, Scocchi M, Wilson DN Tags: Antimicrob Agents Chemother Source Type: research

Chromosomally Encoded mcr-5 in Colistin non-susceptible Pseudomonas aeruginosa.
Abstract Whole genome sequencing (WGS) of historical Pseudomonas aeruginosa clinical isolates identified a chromosomal copy of mcr-5 within a Tn3-like transposon in P. aeruginosa MRSN 12280. The isolate was non-susceptible to colistin by broth microdilution and genome analysis revealed no mutations known to confer colistin resistance. To the best of our knowledge, this is the first report of mcr in colistin non-susceptible P. aeruginosa. PMID: 29844041 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - May 29, 2018 Category: Microbiology Authors: Snesrud E, Maybank R, Kwak YI, Jones AR, Hinkle MK, Mc Gann P Tags: Antimicrob Agents Chemother Source Type: research

Lipopeptide Paenipeptin Analogues Potentiate Clarithromycin and Rifampicin against Carbapenem-Resistant Pathogens.
Abstract Two paenipeptin analogues at 4 μg/ml potentiated clarithromycin and rifampicin against carbapenem-resistant Acinetobacter baumannii and Klebsiella pneumoniae strains. The combined treatment significantly increased their antibacterial efficacy in a microbiological medium and in human serum in vitro at therapeutically-relevant concentrations. Moreover, these two paenipeptins analogues showed low cytotoxicity against a human kidney cell line. Therefore, the combination therapy with paenipeptins may be an option for the treatment of antibiotic-resistant bacterial infections. PMID: 29844042 [PubMed - a...
Source: Antimicrobial Agents and Chemotherapy - May 29, 2018 Category: Microbiology Authors: Moon SH, Huang E Tags: Antimicrob Agents Chemother Source Type: research

Comparison of in vitro activity and MIC distributions between the novel oxazolidinone delpazolid and linezolid against multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis in China.
In conclusion, in vitro susceptibility testing revealed that delpazolid antibacterial activity is comparable to that of linezolid. A novel mutation within rplD was identified that endowed MTB with linezolid, but not delpazolid, resistance. PMID: 29844043 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - May 29, 2018 Category: Microbiology Authors: Zong Z, Jing W, Shi J, Wen S, Zhang T, Huo F, Shang Y, Liang Q, Huang H, Pang Y Tags: Antimicrob Agents Chemother Source Type: research

Anti-trypanosomal 8-hydroxyl naphthyridines are chelators of divalent transition metals.
Abstract Lack of information regarding the mechanisms of action (MoA) or specific molecular targets of phenotypically active compounds can prove a barrier to their development as chemotherapeutic agents. Here, we report the results of our orthogonal genetic, molecular and biochemical studies to determine the MoA of a novel 7-substituted 8-hydroxy-1,6-naphthyridine (8-HNT) series that display promising activity against Trypanosoma brucei and Leishmania donovani High-throughput loss-of-function genetic screens in T. brucei highlighted two probable zinc transporters associated with resistance to these compounds. Thes...
Source: Antimicrobial Agents and Chemotherapy - May 29, 2018 Category: Microbiology Authors: Wall RJ, Moniz S, Thomas MG, Norval S, Ko EJ, Marco M, Miles TJ, Gilbert IH, Horn D, Fairlamb AH, Wyllie S Tags: Antimicrob Agents Chemother Source Type: research

Disruption of mpl Activates β-Lactamase Production in Stenotrophomonas maltophilia and Pseudomonas aeruginosa Clinical Isolates.
Disruption of mpl Activates β-Lactamase Production in Stenotrophomonas maltophilia and Pseudomonas aeruginosa Clinical Isolates. Antimicrob Agents Chemother. 2018 May 29;: Authors: Calvopiña K, Avison MB Abstract The hyperproduction of chromosomally encoded β-lactamases is a key method of acquired resistance to ceftazidime, aztreonam, and when seen in backgrounds having reduced envelope permeability, carbapenems. Here we show that loss of Mpl, a UDP-muramic acid/peptide ligase, is a common and previously overlooked cause of chromosomally encoded β-lactamase hyperproduction in cli...
Source: Antimicrobial Agents and Chemotherapy - May 29, 2018 Category: Microbiology Authors: Calvopiña K, Avison MB Tags: Antimicrob Agents Chemother Source Type: research

Recommendations to address the difficulties encountered when determining linezolid resistance from whole genome sequencing data.
Abstract Mutations associated with linezolid resistance within the V domain of 23S rRNA are annotated using an Escherichia coli numbering system. The 23S rRNA gene varies in length, nucleotide sequence and copy number between bacterial species. Consequently, this numbering system is not intuitive and can lead to confusion when locating mutation sites using whole genome sequencing data. Using the mutation G2576T as an example, we demonstrate the difficulties associated with using the E. coli numbering system. PMID: 29844046 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - May 29, 2018 Category: Microbiology Authors: Beukers AG, Hasman H, Hegstad K, van Hal SJ Tags: Antimicrob Agents Chemother Source Type: research

Clofazimine for the treatment of Mycobacterium kansasii.
Abstract Mycobacterium kansasii pulmonary infection is global problem. Standard combination therapy consists of isoniazid 300 mg/day, rifampin 600 mg/day, and ethambutol 15 mg/kg/day for 18 months. Co-incubation of M. kansasii with different clofazimine concentrations over 7 days in test-tubes resulted in maximal kill (Emax) of 2.03 log10 CFU/mL below day 0. The concentration associated with Emax was 110 times the minimum inhibitory concentration. Next, the effect of human-like concentration-time profiles of clofazimine human-equivalent doses ranging between 0 to 200 mg daily for 21 days were examined in the intra...
Source: Antimicrobial Agents and Chemotherapy - May 29, 2018 Category: Microbiology Authors: Srivastava S, Gumbo T Tags: Antimicrob Agents Chemother Source Type: research

Iron restriction to clinical isolates of Candida albicans by the novel chelator DIBI inhibits growth and increases sensitivity to azoles in vitro and in vivo in a murine model of experimental vaginitis.
This study was aimed at establishing whether withholding iron by currently used medical iron chelators and the novel chelator DIBI could restrict growth and also enhance the activity of azoles against clinical isolates of C. albicans DIBI but not deferoxamine or deferiprone, inhibited growth of C. albicans at relatively low concentrations in vitro and this inhibition was reversed by iron addition. DIBI in combination with various azoles demonstrated stronger growth inhibition than the azoles alone and greatly prolonged inhibition of cell multiplication. In addition, administration of DIBI along with fluconazole (FLC) to mi...
Source: Antimicrobial Agents and Chemotherapy - May 29, 2018 Category: Microbiology Authors: Savage KA, Parquet MDC, Allan DS, Davidson RJ, Holbein BE, Lilly EA, Fidel PL Tags: Antimicrob Agents Chemother Source Type: research

Analysis of the tunicamycin biosynthetic gene cluster of Streptomyces chartreusis reveals new insights into tunicamycin production and immunity.
Abstract The tunicamycin biosynthetic gene cluster of Streptomyces chartreusis consists of 14 genes (tunA-N) with a high degree of apparent translational coupling. Transcriptional analysis revealed that all of these genes are likely to be transcribed as a single operon from two promoters, tunp1 and tunp2. In frame deletion analysis revealed that just six of these genes (tunABCDEH) are essential for tunicamycin production in the heterologous host Streptomyces coelicolor, while five (tunFGKLN) with likely counterparts in primary metabolism are not necessary, but presumably ensure efficient production of the antibiot...
Source: Antimicrobial Agents and Chemotherapy - May 29, 2018 Category: Microbiology Authors: Widdick D, Royer SF, Wang H, Vior NM, Gomez-Escribano JP, Davis BG, Bibb MJ Tags: Antimicrob Agents Chemother Source Type: research

Antimicrobial Efficacy and Safety of a Novel Gas Plasma-Activated Catheter Lock Solution.
In conclusion, PAD represents a novel antibiotic-free, non-cytotoxic lock solution that elicits rapid and broad-spectrum eradication of biofilm-laden microbes and which shows promise for the prevention and treatment of intravascular catheter infections. PMID: 29844050 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - May 29, 2018 Category: Microbiology Authors: Bhatt S, Mehta P, Chen C, Daines DA, Mermel LA, Chen HL, Kong MG Tags: Antimicrob Agents Chemother Source Type: research

Miltefosine has post-antifungal effect and induces apoptosis in Cryptococcus yeasts.
Abstract Cryptococcus spp. are common opportunistic fungal pathogens, particularly in HIV patients. The approved drug miltefosine (MFS) has potential as an alternative antifungal against cryptococcosis; however, the mechanism of action of MFS in Cryptococcus is poorly understood. Here, we examined the effects of MFS on C. neoformans and C. gattii yeasts (planktonic and biofilm lifestyles), to clarify its mechanism of action. MFS presented inhibitory and fungicidal effects against planktonic Cryptococcus cells, with similar activity against dispersion biofilm cells, while sessile biofilm cells were less sensitive t...
Source: Antimicrobial Agents and Chemotherapy - May 29, 2018 Category: Microbiology Authors: Spadari CC, Vila T, Rozental S, Ishida K Tags: Antimicrob Agents Chemother Source Type: research

The Inoculum Effect in the Era of Multidrug Resistance: Minor Differences in Inoculum Have Dramatic Effect on Minimal Inhibitory Concentration Determination.
Abstract The observed MIC may depend on the number of bacteria initially inoculated into the assay. This phenomenon is termed the inoculum effect (IE) and is often most pronounced for β-lactams in strains expressing β-lactamase enzymes. The Clinical and Laboratory Standards Institute (CLSI) recommended inoculum is 5 x 105 CFU mL-1 with an acceptable range of 2-8 x 105 CFU mL-1 IE testing is typically performed using an inoculum 100-fold greater than the CLSI recommended inoculum. Therefore, it remains unknown whether the IE influences MICs during testing performed according to CLSI guidelines. Here, we u...
Source: Antimicrobial Agents and Chemotherapy - May 21, 2018 Category: Microbiology Authors: Smith KP, Kirby JE Tags: Antimicrob Agents Chemother Source Type: research

In vivo and in vitro effects of a ClpP activating antibiotic against vancomycin resistant enterococci.
Abstract Antibiotics with novel bactericidal mechanisms of action are urgently needed. The antibiotic acyldepsipeptide 4 (ADEP4) activates the ClpP protease and causes cells to self-digest. The effects of ADEP4 and ClpP activation have not been sufficiently characterized for the enterococci, which are important pathogens known for high levels of acquired and intrinsic antibiotic resistance. In the present study, ADEP4 was found to be potently active against both Enterococcus faecalis and Enterococcus faecium with an MIC90 of 0.016 μg/ml and 0.031 μg/ml, respectively. ClpP purified from E. faecium was found t...
Source: Antimicrobial Agents and Chemotherapy - May 21, 2018 Category: Microbiology Authors: Brown Gandt A, Griffith EC, Lister IM, Billings LL, Han A, Tangallapally R, Zhao Y, Singh AP, Lee RE, LaFleur MD Tags: Antimicrob Agents Chemother Source Type: research

Clonal spread in Candida glabrata bloodstream isolates and fluconazole resistance affected by prolonged exposure: a 12-year single-center study in Belgium.
Abstract Candida glabrata is a major cause of candidemia in immunocompromised patients and is characterized by a high-level of fluconazole resistance. In the present study, acquisition of antifungal resistance and potential clonal spread of C. glabrata were explored at a single center over a 12-year period by analyzing 187 independent clinical C. glabrata bloodstream isolates. One strain was found to be micafungin resistant due to a mutation in the FKS2 gene. Fluconazole resistance remained stable throughout the period and was observed in 20 (10.7%) of the isolates. Analysis of the antifungal consumption data reve...
Source: Antimicrobial Agents and Chemotherapy - May 21, 2018 Category: Microbiology Authors: Goemaere B, Lagrou K, Spriet I, Hendrickx M, Becker P Tags: Antimicrob Agents Chemother Source Type: research

Oxidative Stress and First-Line Antituberculosis Drug-Induced Hepatotoxicity.
Abstract Hepatotoxicity induced by antituberculosis drugs is a serious adverse reaction with significant morbidity and even rarely mortality. This form of toxicity potentially impacts the treatment outcome of tuberculosis in some patients. Confining to first-line antituberculosis drugs, this review addresses whether and how oxidative stress, and more broadly, disturbance in redox homeostasis alongside mitochondrial dysfunction, may contribute to the hepatotoxicity induced by them. Risk factors for such toxicity that have been identified, in addition to genetic factors, principally include old age, malnutrition, al...
Source: Antimicrobial Agents and Chemotherapy - May 21, 2018 Category: Microbiology Authors: Yew WW, Chang KC, Chan DP Tags: Antimicrob Agents Chemother Source Type: research

The metabolism of piperaquine to its antiplasmodial metabolites and their pharmacokinetic profiles in healthy volunteers.
Abstract As a partner antimalarial for artemisinin drug-based combination therapy (ACT), piperaquine (PQ) can be metabolized into two major metabolites, including piperaquine N-oxide (M1) and N,N-dioxide (M2). To better understand the antimalarial potency of PQ, the antimalarial activity of PQ metabolites (M1 and M2) was studied in vitro (Plasmodium strains Pf3D7 and PfDd2) and in vivo (murine Plasmodium yoelii) in this study. The recrudescence and survival time of infected mice were also recorded after drug treatment. The pharmacokinetic profiles of PQ and its two metabolites (M1 and M2) were investigated in heal...
Source: Antimicrobial Agents and Chemotherapy - May 21, 2018 Category: Microbiology Authors: Liu H, Zhou H, Cai T, Yang A, Zang M, Xing J Tags: Antimicrob Agents Chemother Source Type: research

EUCAST Determination of olorofim (F901318) susceptibility of mould species, method validation and MICs.
up MC Abstract Olorofim is a novel antifungal agent with in vitro activity against Aspergillus and some other moulds. Here we addressed technical aspects for EUCAST olorofim testing and generated contemporary MIC data.EUCAST E.Def 9.3.1 testing was performed comparing two plate preparation methods (serial-dilution in medium (serial-plates) versus pre-dilution in DMSO (ISO-plates)), two lots of olorofim, visual (visual-MIC) versus spectrophotometer (spec-MIC) reading and four polystyrene plates using 34-53 Aspergillus isolates from five genera. Subsequently, olorofim MICs were compared to itraconazole, voriconazole...
Source: Antimicrobial Agents and Chemotherapy - May 21, 2018 Category: Microbiology Authors: Jørgensen KM, Astvad KMT, Hare RK, Arendrup MC Tags: Antimicrob Agents Chemother Source Type: research

High Dose and Delayed Treatment with Bile Acids Ineffective in RML Prion-Infected Mice.
Abstract Prion diseases are a group of neurodegenerative diseases associated with the misfolding of the cellular prion protein (PrPC) into the infectious form (PrPSc). There are currently no treatments for prion disease. Bile acids have the ability to protect hepatocytes from apoptosis and are neuroprotective in animal models of other protein folding neurodegenerative diseases including Huntington's, Parkinson's, and Alzheimer's disease. Importantly, bile acids are approved for clinical use in patients with cirrhosis, and have recently been shown to be safe and possibly effective in pilot trials of patients with a...
Source: Antimicrobial Agents and Chemotherapy - May 21, 2018 Category: Microbiology Authors: Norman G, Campeau J, Sim VL Tags: Antimicrob Agents Chemother Source Type: research

Incidences of Pseudomonas associated Ventilator-associated pneumonia within studies of respiratory tract applications of polymyxin: testing the Stoutenbeek concurrency postulates.
Abstract Regimens containing topical polymyxin appear highly effective at preventing Ventilator-associated pneumonia (VAP) overall and more-so, gram negative VAP. However, Soutenbeek's postulates, that VAP incidences within studies of topical antibiotics would depend on the context of whether the component (control and intervention) groups of each study were concurrent versus non-concurrent, remain untested.The literature was searched for concurrent control (CC) versus non-concurrent control (NCC) designed studies of respiratory tract applications of topical polymyxin to mechanically ventilated (MV) patients that ...
Source: Antimicrobial Agents and Chemotherapy - May 21, 2018 Category: Microbiology Authors: Hurley JC Tags: Antimicrob Agents Chemother Source Type: research

Interaction of Bacterial Phenazines with Colistimethate in Bronchial Epithelial Cells.
We report here on testing paired combinations of four Pseudomonas aeruginosa VF phenazine toxins, pyocyanin (PYO), 1-hydroxyphenazine (1-HP), phenazine-1-carboxylic acid (PCA), phenazine-1-carboxamide (PCN), and two commonly prescribed polymyxin drugs, colistimethate (CMS)/colistin and polymyxin B, in three human airway cell lines, BEAS-2B, HBE-1, and CFT-1. Cytotoxicities of individual antibiotics, toxins, and their combinations were evaluated by simultaneous measurement of mitochondrial metabolic, total transcriptional/translational, and the Nrf2 stress response regulator activities in treated cells. Two phenazines, PYO ...
Source: Antimicrobial Agents and Chemotherapy - May 21, 2018 Category: Microbiology Authors: Mossine VV, Chance DL, Waters JK, Mawhinney TP Tags: Antimicrob Agents Chemother Source Type: research

Pharmacokinetics of piperaquine and safety profile of dihydroartemisinin-piperaquine co-administered with antiretroviral therapy in malaria-uninfected HIV-positive Malawian adults.
Abstract There are limited data on the pharmacokinetic and safety profiles of dihydroartemisinin-piperaquine (DHA-PQ) among human immunodeficiency virus infected (HIV+) individuals taking antiretroviral therapy (ART). In a two step (parallel-group) pharmacokinetic trial with intensive blood sampling, we compared area under the concentration-time curve (AUC0-28 days) and safety outcomes of piperaquine among malaria-uninfected HIV+ adults. In step 1, half the adult dose of DHA-PQ was administered for three days as an intitial safety check in four groups (n=6/group) of HIV+ adults (age≥18 years): (i) antiretrovira...
Source: Antimicrobial Agents and Chemotherapy - May 21, 2018 Category: Microbiology Authors: Banda CG, Dzinjalamala F, Mukaka M, Mallewa J, Maiden V, Terlouw DJ, Lalloo DG, Khoo SH, Mwapasa V Tags: Antimicrob Agents Chemother Source Type: research

Translation elongation factor 4 (LepA) contributes to tetracycline susceptibility by stalling elongating ribosomes.
Abstract Even though elongation factor 4 (EF4) is the third most conserved protein in bacteria, its physiological functions remain largely unknown and its proposed molecular mechanisms are conflicting among previous studies. In the present study we show that growth of an Escherichia coli strain is more susceptible to tetracycline than its EF4 knockout strain. In consistence with previous studies, our results suggested that EF4 affects ribosome biogenesis when tetracycline is present. Through ribosome profiling analysis, we discovered that EF4 causes 1-nucleotide shifting of ribosomal footprints on mRNA when cells ...
Source: Antimicrobial Agents and Chemotherapy - May 21, 2018 Category: Microbiology Authors: Liu B, Chen C Tags: Antimicrob Agents Chemother Source Type: research

In vitro and in vivo activity of contezolid (MRX-I) against Mycobacterium tuberculosis.
Abstract The in vitro activity of contezolid (MRX-I) against clinical isolates of M. tuberculosis was evaluated using a microtiter broth dilution assay. MRX-I was as effective in vitro as linezolid (LZD). MRX-I and LZD were subsequently studied in BALB/c mice infected intranasally with M. tuberculosis Erdman. MRX-I and LZD at 100mg/kg significantly reduced the bacterial load in lungs compared to the untreated early and late controls. PMID: 29784848 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - May 21, 2018 Category: Microbiology Authors: Shoen C, DeStefano M, Hafkin B, Cynamon M Tags: Antimicrob Agents Chemother Source Type: research