Electrostatic-Mediated Affinity Tuning of Lysostaphin Accelerates Bacterial Lysis Kinetics and Enhances in Vivo Efficacy.
Abstract Drug-resistant bacterial pathogens are a serious threat to global health, and antibacterial lysins are at the forefront of innovative treatments for these life-threatening infections. While lysins' general mechanism of action is well understood, the design principles that might enable engineering of performance-enhanced variants are still being formulated. Here we report a detailed analysis of molecular determinants underlying the in vivo efficacy of lysostaphin, a canonical anti-MRSA lysin. Systematic analysis of bacterial binding, growth inhibition, lysis kinetics, and in vivo therapeutic efficacy revea...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Zhao H, Eszterhas S, Furlon J, Cheng H, Griswold KE Tags: Antimicrob Agents Chemother Source Type: research

Development and Characterization of Monoolein-Based Liposomes of Carvacrol, Cinnamaldehyde, Citral or Thymol with anti-Candida Activities.
In conclusion, carvacrol and thymol liposomes possess high stability, low cytotoxicity, and antifungal activity that acts synergistically with macrophages. PMID: 33468460 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Miranda-Cadena K, Dias M, Costa-Barbosa A, Collins T, Marcos-Arias C, Eraso E, Pais C, Quindós G, Sampaio P Tags: Antimicrob Agents Chemother Source Type: research

Modulation of Human Beta-Defensin 2 Expression by Pathogenic Neisseria meningitidis and Commensal Lactobacilli.
Abstract Antimicrobial peptides (AMPs) play an important role in the defense against pathogens by targeting and killing invading microbes. Some pathogenic bacteria have been shown to negatively regulate AMP expression, while several commensals may induce AMP expression. The expression of certain AMPs, such as human beta-defensin 2 (hBD2), can be induced via nuclear factor NF-κB, which in turn is negatively controlled by tumor necrosis factor alpha-induced protein 3 (TNFAIP3, or A20). In this work, we examined the expression of hBD1 and hBD2 during coincubation of pharyngeal epithelial cells with pathogenic N...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Wassing GM, Ilehag N, Frey J, Jonsson AB Tags: Antimicrob Agents Chemother Source Type: research

The Pup-Proteasome System Protects Mycobacteria from Antimicrobial Antifolates.
Abstract Protein turnover via the Pup-proteasome system (PPS) is essential for nitric oxide resistance and virulence of Mycobacterium tuberculosis, the causative agent of tuberculosis. Our study revealed components of PPS as novel determinants of intrinsic antifolate resistance in both M. tuberculosis and non-pathogenic M. smegmatis Lack of expression of the prokaryotic ubiquitin-like protein (Pup) or the ligase, PafA, responsible for ligating Pup to its protein targets, enhanced antifolate susceptibility in M. smegmatis Cross-species expression of M. tuberculosis homologs restored wild type resistance to M. smegm...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Guzzo MB, Li Q, Nguyen HV, Boom WH, Nguyen L Tags: Antimicrob Agents Chemother Source Type: research

Carbapenem use is driving the evolution of IMiPenemase (IMP)-1 variants.
Abstract Metallo-β-lactamases (MBLs) are a growing clinical threat because they inactivate nearly all β-lactam-containing antibiotics, and there are no clinically-available inhibitors. A significant number of variants have already emerged for each MBL subfamily. To understand the evolution of IMiPenemase (IMP) genes (bla IMP) and their clinical impact, twenty clinically-derived IMP-1 like variants were obtained using site-directed mutagenesis and expressed in a uniform genetic background in Escherichia coli DH10B. Strains of IMP-1-like variants harboring S262G or V67F substitutions exhibited increased re...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Cheng Z, Bethel CR, Thomas PW, Shurina BA, Alao JP, Thomas CA, Yang K, Zhang H, Sturgill AM, Kravats AN, Page RC, Fast W, Bonomo RA, Crowder MW Tags: Antimicrob Agents Chemother Source Type: research

Inhibition of Arenaviruses by Combinations of Orally Available Approved Drugs.
In this report, we demonstrate that arbidol, an approved influenza antiviral previously shown to inhibit EBOV, LASV, and many other viruses, inhibits murine leukemia (MLV) reporter viruses pseudotyped with the fusion glycoproteins (GP) of other arenaviruses [Junin (JUNV), lymphocytic choriomeningitis virus (LCMV), and Pichinde (PICV)]. Arbidol and other approved drugs including aripiprazole, amodiaquine, sertraline, and niclosamide also inhibit infection of cells by infectious PICV, and arbidol, sertraline and niclosamide inhibit infectious LASV. Combining arbidol with aripiprazole or sertraline results in synergistic supp...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Herring S, Oda JM, Wagoner J, Kirchmeier D, O'Connor A, Nelson EA, Huang Q, Liang Y, Evans DeWald L, Johansen LM, Glass PJ, Olinger GG, Ianevski A, Aittokallio T, Paine MF, Fink SL, White JM, Polyak SJ Tags: Antimicrob Agents Chemother Source Type: research

Dose-fractionation of moxifloxacin for the treatment of tuberculosis: impact of dosing interval and elimination half-life on microbial kill and resistance suppression.
We examined 12, 24 and 48 hr dosing intervals with doses of 200 mg, 400 mg and 800 mg for each interval, respectively. Within each interval, we had an arm where half-lives of 12, 8 and 4 hr were simulated. We attempted to keep the CAvg (AUC) constant across arms. We found that susceptible bacterial load decline was linked to CAvg, as we had indicated previously. Resistance suppression, a non-monotonic function, had CMin as the linked index. The 48 hr interval with the 4 hr half-life had the largest less-susceptible population. Balancing bacterial kill, resistance suppression, toxicity (CPeak-linked) and adherence, we concl...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Drusano GL, Rogers S, Brown D, Peloquin CA, Neely M, Yamada W, Kim S, Almoslem M, Schmidt S, Louie A Tags: Antimicrob Agents Chemother Source Type: research

In vitro resistance and evolution of resistance to tavaborole in Trichophyton rubrum.
In this study, we analyzed the in vitro emergence/evolution of resistance against tavaborole in Trichophyton rubrum When T. rubrum strains were propagated on media containing the MIC of tavaborole, spontaneous resistant mutants were isolated at a frequency of 10-8 The frequency was almost 100-fold higher following fungal growth in the presence of a sub-inhibitory tavaborole concentration (0.5-fold the MIC) for ten transfers. All collected mutants showed similar 4- to 8-fold increase in the drug minimal inhibitory concentration. No cross-resistance to other antifungals was evidenced. PMID: 33468466 [PubMed - as supplie...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Mazzantini D, Celandroni F, Calvigioni M, Lupetti A, Ghelardi E Tags: Antimicrob Agents Chemother Source Type: research

The antibiotic negamycin crosses the bacterial cytoplasmic membrane by multiple routes.
uml;tz-Oesterhelt H Abstract Negamycin is a natural pseudo-dipeptide antibiotic with promising activity against Gram-negative and Gram-positive bacteria, including Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus, and good efficacy in infection models. It binds to ribosomes with a novel binding mode, stimulating miscoding and inhibiting ribosome translocation. We were particularly interested in studying how the small, positively charged natural product reaches its cytoplasmic target in Escherichia coli Negamycin crosses the cytoplasmic membrane by multiple routes depending on environmental con...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Hörömpöli D, Ciglia C, Glüsenkamp KH, Haustedt LO, Falkenstein-Paul H, Bendas G, Berscheid A, Brötz-Oesterhelt H Tags: Antimicrob Agents Chemother Source Type: research

Daptomycin resistance in Enterococcus faecium can be delayed by disruption of the LiaFSR stress response pathway.
Abstract LiaFSR signaling plays a major role in mediating daptomycin (DAP) resistance in enterococci, and the lack of a functional LiaFSR pathway leads to DAP hypersusceptibility. Using in vitro experimental evolution, we evaluated how Enterococcus faecium with a liaR response regulator gene deletion evolved DAP resistance. We found that knocking out LiaFSR signaling significantly delayed the onset of resistance, but resistance could emerge eventually through a variety of alternate mechanisms that were influenced by the environment. PMID: 33468468 [PubMed - as supplied by publisher] (Source: Antimicrobial Age...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Prater AG, Mehta HH, Beabout K, Supandy A, Miller WR, Tran TT, Arias CA, Shamoo Y Tags: Antimicrob Agents Chemother Source Type: research

Identification of Tn6835 and a Novel Genomic Island MMGI-1 in a Pan-Resistant Morganella morganii Strain.
Abstract Morganella morganii is a member of Morganellaceae that shares closest features with Proteus and Providencia genera (1) and is widespread in the environment and the intestinal tracts of animals and humans.…. PMID: 33468469 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Xiang R, Li M Tags: Antimicrob Agents Chemother Source Type: research

Boromycin has potent anti-Toxoplasma and anti-Cryptosporidium activity.
Abstract Toxoplasma gondii and Cryptosporidium parvum, members of the phylum Apicomplexa, are significant pathogens of both humans and animals worldwide for which new and effective therapeutics are needed. Here we describe the activity of the antibiotic boromycin against Toxoplasma and Cryptosporidium Boromycin potently inhibited intracellular proliferation of both T. gondii and C. parvum at half maximal effective concentrations (EC50) of 2.27 nM and 4.99 nM, respectively. Treatment of extracellular T. gondii tachyzoites with 25 nM of boromycin for 30 mins suppressed 84% of parasite growth, but T. gondii tachyzoit...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Abenoja J, Cotto-Rosario A, O'Connor R Tags: Antimicrob Agents Chemother Source Type: research

Assessment of piperacillin-tazobactam-meropenem synergy against serine carbapenemase producing Enterobacterales using time kill assays.
Abstract Synergy between piperacillin-tazobactam and meropenem against KPC-producing Klebsiella pneumoniae was recently demonstrated. We sought to test the combination against a broader range of serine carbapenemase producers. We tested the combination against 10 KPC-producing E. coli and 10 OXA-48 family producing K. pneumoniae Antibiotic concentrations used are achievable in critically ill patients. The combination was synergistic against 7/10 KPC producers and in 9/10 OXA-48 producers. There was no synergy detected in control isolates producing NDM-1. PMID: 33468471 [PubMed - as supplied by publisher] (Sou...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Lawandi A, Leite GC, Cheng MP, Lefebvre B, Longtin J, Lee TC Tags: Antimicrob Agents Chemother Source Type: research

Synergistic rifabutin and colistin reduce emergence of resistance when treating Acinetobacter baumannii.
Abstract Recently, we reported rifabutin hyper-activity against Acinetobacter baumannii We sought to characterize potential interactions between rifabutin and colistin, the last resort drug for carbapenem-resistant infections. Rifabutin and colistin were synergistic in vitro and in vivo, and low dose colistin significantly suppressed emergence of resistance to rifabutin. Thus, this combination is a promising therapeutic option for highly resistant A. baumannii infections. PMID: 33468472 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Cheng J, Yan J, Reyna Z, Slarve M, Lu P, Spellberg B, Luna B Tags: Antimicrob Agents Chemother Source Type: research

Deletion of PknG abates reactivation of latent Mycobacterium tuberculosis in mice.
Abstract Eradication of tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), has been a challenge due to its uncanny ability to survive dormantly inside the host granulomas for decades. Mtb rewires its metabolic and redox regulatory networks to survive in the hostile hypoxic and nutrient-limiting environment, facilitating the formation of the drug-tolerant persisters. Previously, we showed that Protein Kinase G (PknG), a virulence factor required for the lysosomal escape, aids in metabolic adaptation thereby promoting the survival of non-replicating mycobacterium. Here, we sought to investigate the thera...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Khan MZ, Nandicoori VK Tags: Antimicrob Agents Chemother Source Type: research

In vivo targeting of E. coli with vancomycin-arginine.
Abstract The ability of vancomycin-arginine (V-r) to extend the spectrum of activity of glycopeptides to gram-negative bacteria was investigated. Its MIC towards E. coli including β-lactamase expressing Ambler classes A, B, and D was 8-16μg/ml. Addition of 8×MIC V-r to E. coli was acutely bactericidal and associated with a low frequency of resistance (7 log10 CFU/g in a thigh muscle model. These data warrant further development of V-r in combatting E. coli, including resistant forms. PMID: 33468474 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Neville LF, Shalit I, Warn PA, Scheetz MH, Sun J, Chosy MB, Wender PA, Cegelski L, Rendell JT Tags: Antimicrob Agents Chemother Source Type: research

Tetracycline resistance mediated by tet(M) has variable Integrative Conjugative Element composition in Mycoplasma hominis isolated in the United Kingdom from 2005-2015.
We examined antimicrobial susceptibility (AST) on strains archived between 2005-2015 submitted to the Public Health England reference laboratory and determined the underlying mechanism of resistance by whole genome sequencing (WGS). Archived M. hominis strains included 32/115 from invasive infection (sepsis, CSF, peritoneal and pleural fluid) over the 10-year period (6.4% of all samples submitted between 2010-2015 were positive). No clindamycin resistance was detected, while two strains were resistant to moxifloxacin and levofloxacin (resistance mutations: S83L or E87G in gyrA and S81I or E84V in parC). One of these strain...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Chalker VJ, Sharratt MG, Rees C, Bell OH, Portal E, Sands K, Payne MS, Spiller OB Tags: Antimicrob Agents Chemother Source Type: research

Therapeutic potential of Fosmanogepix (APX001) for intra-abdominal candidiasis: from lesion penetration to efficacy in a mouse model.
Abstract Intra-abdominal candidiasis (IAC) is one of the most common yet underappreciated form of invasive candidiasis. IAC is difficult to treat, and therapeutic failure and drug resistant breakthrough infections are common in some institutions despite the use of echinocandins as first line agents. Fosmanogepix (FMGX, formerly APX001) is a first-in-class antifungal prodrug that can be administered both intravenously and orally. FMGX is currently in Phase 2 clinical development for the treatment of life-threatening invasive fungal infections. To explore the pharmacological property and therapeutic potential of FMG...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Lee A, Wang N, Carter CL, Zimmerman M, Dartois V, Shaw KJ, Perlin DS, Zhao Y Tags: Antimicrob Agents Chemother Source Type: research

Semi-mechanistic pharmacokinetic and pharmacodynamic modelling of piperaquine in a volunteer infection study with Plasmodium falciparum blood-stage malaria.
Abstract Dihydroartemisinin-piperaquine is a recommended first-line artemisinin combination therapy for falciparum malaria. Piperaquine is also under consideration for other antimalarial combination therapies. The aim of this study was to develop a pharmacokinetic-pharmacodynamic model that could be used to optimize the use of piperaquine in new antimalarial combination therapies. The pharmacokinetic-pharmacodynamic model was developed using data from a previously reported dose-ranging study where 24 healthy volunteers were inoculated 1,800 blood-stage Plasmodium falciparum parasites. All volunteers received a sin...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Wattanakul T, Baker M, Mohrle J, McWhinney B, Hoglund RM, McCarthy JS, Tarning J Tags: Antimicrob Agents Chemother Source Type: research

The benzimidazole SPR719 shows promising concentration-dependent activity and synergy against nontuberculous mycobacteria.
Abstract Nontuberculous mycobacterial pulmonary disease (NTM-PD) is emerging worldwide. Currently recommended multidrug treatment regimens yield poor outcomes and new drugs and regimens are direly needed. SPR719, the active moiety of SPR720 is a new benzimidazole antibiotic with limited data on antimycobacterial activity.We determined MICs and MBCs against 138 clinical and reference strains of M. avium complex (MAC), M. kansasii, M. abscessus, M. xenopi, M. malmoense and M. simiae and determined synergy with antimycobacterial drugs by checkerboard titrations. To study pharmacodynamics, we performed time-kill kinet...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Pennings LJ, Ruth MM, Wertheim HFL, van Ingen J Tags: Antimicrob Agents Chemother Source Type: research

Characterization of an IncFIB/IncHI1B plasmid encoding efflux pump TMexCD1-TOprJ1 in a clinical tigecycline and carbapenem-resistant Klebsiella pneumoniae strain.
Abstract A novel plasmid-encoded resistance-nodulation-division efflux pump, TMexCD1-TOprJ1, conferring resistance to multiple drugs including tigecycline has been identified in Klebsiella pneumoniae strains recently (1, 2).…. PMID: 33468479 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Yang X, Ye L, Chan EW, Zhang R, Chen S Tags: Antimicrob Agents Chemother Source Type: research

Variability of Hydroxy-Itraconazole in Relation to Itraconazole Bloodstream Concentrations.
Abstract We analyzed the relationship between itraconazole (ITZ) and hydroxy-itraconazole (OH-ITZ) levels in 1223 human samples. Overall, there was a statistically significant correlation between ITZ and OH-ITZ levels (correlation coefficient 0.7838), and OH-ITZ levels were generally higher than that of ITZ (median OH-ITZ:ITZ ratio 1.73; range 0.13 to 8.96). However, marked variability was observed throughout the range of ITZ concentrations. Thus, it is difficult to predict OH-ITZ concentrations based solely on ITZ levels. PMID: 33468480 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Wiederhold NP, Schwartz IS, Patterson TF, Thompson GR Tags: Antimicrob Agents Chemother Source Type: research

Ethylzingerone, a Novel Compound with Antifungal Activity.
Abstract Preservatives increase the shelf life of cosmetic products by preventing growth of contaminating microbes, including bacteria and fungi. In recent years, the Scientific Committee on Consumer Safety (SCCS) has recommended the ban or restricted use of a number of preservatives due to safety concerns. Here, we characterize the antifungal activity of Ethylzingerone (Hydroxyethoxyphenyl butanone, HEPB), an SCCS-approved new preservative for use in rinse-off, oral care and leave-on cosmetic products. We show that HEPB significantly inhibits growth of Candida albicans, Candida glabrata and Saccharomyces cerevisi...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Rossignol T, Znaidi S, Chauvel M, Westgate R, Decourty L, Menard-Szczebara F, Cupferman S, Dalko-Scisba M, Barnes R, Maillard JY, Saveanu C, d'ENFERT C Tags: Antimicrob Agents Chemother Source Type: research

Identification of Antifungal Compounds against Multidrug Resistant Candida auris Utilizing a High Throughput Drug Repurposing Screen.
Abstract Candida auris is an emerging fatal fungal infection that has resulted in several outbreaks in hospitals and care facilities. Current treatment options are limited by the development of drug resistance. Identifying new pharmaceuticals to combat these drug-resistant infections will thus be required to overcome this unmet medical need. We have established a bioluminescent ATP-based assay to identify new compounds and potential drug combinations showing effective growth inhibition against multiple strains of multidrug resistant Candida auris The assay is robust and suitable for assessing large compound collec...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Cheng YS, Roma JS, Shen M, Fernandes CM, Tsang PS, Forbes HE, Boshoff H, Lazzarini C, Del Poeta M, Zheng W, Williamson PR Tags: Antimicrob Agents Chemother Source Type: research

Physicochemical and Structural Parameters Contributing to the Antibacterial Activity and Efflux Susceptibility of Small Molecule Inhibitors of Escherichia coli.
Abstract Discovering new Gram-negative antibiotics has been a challenge for decades. This has been largely attributed to a limited understanding of the molecular descriptors governing Gram-negative permeation and efflux evasion. Herein, we address the contribution of efflux using a novel approach that applies multivariate analysis, machine learning, and structure-based clustering to some 4,500 actives from a small molecule screen in efflux-compromised Escherichia coli We employed principal-component analysis and trained two decision tree-based machine learning models to investigate descriptors contributing to the ...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: El Zahed SS, French S, Farha MA, Kumar G, Brown ED Tags: Antimicrob Agents Chemother Source Type: research

In-Vitro Study of the Synergistic Effect of an Enzyme Cocktail and Antibiotics against Biofilms in a Prosthetic Joint Infection Model.
In this study, we explore the effect of a tri-enzymatic cocktail (TEC) consisting of an endo-1,4-β-d-glucanase, a β-1,6-hexosaminidase, and an RNA/DNA nonspecific endonuclease combined with antibiotics of different classes against biofilms of S. aureus, S. epidermidis, and E. coli grown on Ti6Al4V substrates. Biofilms were grown in TSB with 10g/L glucose and 20g/L NaCl (TGN). Mature biofilms were assigned to a control group or treated with the TEC for 30 min, then either analyzed or reincubated for 24h in TGN or TGN with antibiotics. The cytotoxicity of the TEC was assayed against MG-63 osteoblasts, primary murin...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Poilvache H, Ruiz-Sorribas A, Cornu O, Van Bambeke F Tags: Antimicrob Agents Chemother Source Type: research

Limited MDR efflux pump overexpression among multidrug-resistant Escherichia coli of ST131.
Abstract Gram-negative bacteria partly rely on efflux pumps to facilitate growth under stressful conditions and to increase resistance to a wide variety of commonly used drugs. In recent years E. coli ST131 has emerged as a major cause of extraintestinal infection frequently exhibiting an MDR phenotype. The contribution of efflux to MDR in emerging E. coli MDR clones however, is not well studied. We characterized strains from an international collection of clinical MDR-E. coli isolates by MIC testing with and without the addition of the AcrAB-TolC efflux inhibitor 1-(1-naphthylmethyl)-piperazine (NMP). MIC data fo...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Camp J, Schuster S, Vavra M, Schweigger T, Rossen JWA, Reuter S, Kern WV Tags: Antimicrob Agents Chemother Source Type: research

The Role of New Posaconazole Formulations in the Treatment of Candida albicans Infections:Data from an in Vitro Pharmacokinetic-Pharmacodynamic Model.
Conclusion Posaconazole i.v./tablet formulations may have a role in the therapy of invasive infections by wild-type C. albicans isolates provided a steady state is reached fast. A PK-PD susceptibility breakpoint at the ECOFF of 0.06 mg/liter was determined. PMID: 33468486 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Beredaki MI, Arendrup MC, Andes D, Mouton JW, Meletiadis J Tags: Antimicrob Agents Chemother Source Type: research

Monitoring the epidemiology and antifungal resistance of yeasts causing fungaemia in a tertiary care hospital in Madrid, Spain. Any relevant changes in the last 13 years?
, Escribano P, Guinea J Abstract Updated analysis on yeast isolates causing fungaemia in patients admitted to a tertiary hospital in Madrid, Spain, over a 13-year period.We studied 896 isolates associated to 872 episodes of fungaemia in 857 hospitalized patients between January 2007 and December 2019. Antifungal susceptibility was assessed by EUCAST EDef 7.3.2. Mutations conferring azole and echinocandin resistance were further studied, and genotyping of resistant clones performed with species-specific microsatellite markers.Candida albicans (45.8%) was the most frequently identified species, followed by the Candi...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Díaz-García J, Mesquida A, Sánchez-Carrillo C, Reigadas E, Muñoz P, Escribano P, Guinea J Tags: Antimicrob Agents Chemother Source Type: research

Adaptive Processes Change as Multiple Functions Evolve.
low M Abstract Epistasis influences the gene-environment interactions that shape bacterial fitness through antibiotic exposure which can ultimately affect the availability of certain resistance phenotypes to bacteria. The substitutions present within bla TEM-50 confer both cephalosporin and β-lactamase inhibitor resistance. We wanted to compare the evolution of bla TEM-50 with another variant, blaTEM -85, which differs in that blaTEM -85 contains only substitutions that contribute to cephalosporin resistance. Differences between the landscapes and epistatic interactions of these TEM variants are important for...
Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Mira PM, Østman B, Guzman-Cole C, Sindi S, Barlow M Tags: Antimicrob Agents Chemother Source Type: research

Structural and biochemical characterization of the novel CTX-M-151 extended-spectrum β-lactamase and its inhibition by Avibactam.
Structural and biochemical characterization of the novel CTX-M-151 extended-spectrum β-lactamase and its inhibition by Avibactam. Antimicrob Agents Chemother. 2021 Jan 11;: Authors: Ghiglione B, Rodríguez MM, Brunetti F, Papp-Wallace KM, Yoshizumi A, Ishii Y, Bonomo RA, Gutkind G, Klinke S, Power P Abstract The diazabicyclooctane (DBO) inhibitor, avibactam (AVI), reversibly inactivates most serine-β-lactamases including the CTX-M β-lactamases. Currently, more than 230 CTX-M unique members distributed in five clusters with less than 5% amino acid sequence divergence within each gr...
Source: Antimicrobial Agents and Chemotherapy - January 11, 2021 Category: Microbiology Authors: Ghiglione B, Rodríguez MM, Brunetti F, Papp-Wallace KM, Yoshizumi A, Ishii Y, Bonomo RA, Gutkind G, Klinke S, Power P Tags: Antimicrob Agents Chemother Source Type: research

The C2H2 Transcription Factor SltA Contributes to Azole Resistance by Coregulating the Expression of the Drug Target Erg11A and the Drug Efflux Pump Mdr1 in Aspergillus fumigatus.
Abstract The emergence of azole-resistant fungal pathogens has posed a great threat to public health worldwide. Although the molecular mechanism of azole resistance has been extensively investigated, the potential regulators of azole resistance remain largely unexplored. Here we identified a new function of the fungal specific C2H2 zinc finger transcription factor SltA (involved in salt-tolerance pathway) in the regulation of azole resistance of the human fungal pathogen Aspergillus fumigatus Lack of SltA results in an itraconazole hypersusceptibility phenotype. Transcriptional profiling combined with LacZ reporte...
Source: Antimicrobial Agents and Chemotherapy - January 11, 2021 Category: Microbiology Authors: Du W, Zhai P, Wang T, Bromley MJ, Zhang Y, Lu L Tags: Antimicrob Agents Chemother Source Type: research

Activity of Cefepime in Combination with the novel ß-Lactamase inhibitor taniborbactam (VNRX-5133) against ESBL-producing isolates in in vitro checkerboard assays.
Conclusion The combination cefepime/taniborbactam demonstrated a potent activity against ESBL isolates restoring susceptibility of all Enterobacterales and 2/3 of P. aeruginosa isolates. PMID: 33431413 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 11, 2021 Category: Microbiology Authors: Kloezen W, Melchers RJ, Georgiou PC, Mouton JW, Meletiadis J Tags: Antimicrob Agents Chemother Source Type: research

In Vivo Activity of WCK 4282 (High-Dose Cefepime/Tazobactam) against Serine- β-lactamase-Producing Enterobacterales and Pseudomonas aeruginosa in the Neutropenic Murine Lung Infection Model.
Conclusion: WCK 4282 produced potent in vivo activity against ESBL- and cephalosporinase-producing Enterobacterales and P. aeruginosa, and potential activity against OXA-48-like-producing Enterobacterales in a neutropenic pneumonia model. PMID: 33431414 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 11, 2021 Category: Microbiology Authors: Lasko MJ, Abdelraouf K, Nicolau DP Tags: Antimicrob Agents Chemother Source Type: research

Analysis of multidrug resistance in Staphylococcus aureus with a machine learning generated antibiogram.
YT Abstract Multidrug resistance (MDR) surveillance consists of reporting MDR prevalence and MDR phenotypes. Detailed knowledge of the specific associations underlying MDR patterns can allow antimicrobial stewardship programs to accurately identify clinically relevant resistance patterns. We applied machine learning and graphical networks to quantify and visualize associations between resistance traits in a set of 1,091 Staphylococcus aureus isolates collected from one New York hospital between 2008 and 2018. Antimicrobial susceptibility testing was performed using reference broth microdilution. The isolates were...
Source: Antimicrobial Agents and Chemotherapy - January 11, 2021 Category: Microbiology Authors: Cazer CL, Westblade LF, Simon MS, Magleby R, Castanheira M, Booth JG, Jenkins SG, Gröhn YT Tags: Antimicrob Agents Chemother Source Type: research

Evaluation of Synergistic Activity of Isavuconazole or Voriconazole plus Anidulafungin and the Occurrence and Genetic Characterisation of Candida auris Detected in a Surveillance Program.
Abstract A total of 15 Candida auris isolates from the SENTRY Antimicrobial Surveillance Program between 2006 and 2019 were combined with 21 isolates from other collections for the evaluation of antifungal susceptibility and synergy against anidulafungin plus voriconazole or isavuconazole using the checkerboard method. Surveillance isolates were analyzed for genetic relatedness and resistance mechanisms. Applying the tentative statistical epidemiological cutoff values and the Centers for Disease Control tentative breakpoints, 32/36 isolates were resistant to fluconazole, 5/36 were resistant to amphotericin B, 5/36...
Source: Antimicrobial Agents and Chemotherapy - January 11, 2021 Category: Microbiology Authors: Pfaller MA, Messer SA, Deshpande LM, Rhomberg PR, Utt EA, Castanheira M Tags: Antimicrob Agents Chemother Source Type: research

Activity of Clofazimine and TBI-166 against Mycobacterium tuberculosis, in different administration intervals in mouse tuberculosis models.
Abstract Clofazimine (CFZ) and TBI-166 belong to the riminophenazine class of antimicrobial agent. TBI-166 exhibited promising anti-tuberculosis activity in vitro and in animal models, is currently under phase I clinical development for the treatment of tuberculosis in China. To identify an optimal dosing regimen to support further clinical development of TBI-166, the efficacy of CFZ and TBI-166 were evaluated in two aerosol infection models utilizing BALB/c and C3HeB/FeJNju mice. TBI-166 and CFZ were dosed at 20 mg/kg daily for two weeks, followed by QD (once daily), TIW (thrice weekly) and BIW (twice weekly) for...
Source: Antimicrobial Agents and Chemotherapy - January 11, 2021 Category: Microbiology Authors: Zhu H, Fu L, Wang B, Chen X, Zhao J, Huang H, Lu Y Tags: Antimicrob Agents Chemother Source Type: research

An Integrated HOCl-Producing E-Scaffold Is Active Against Monomicrobial and Polymicrobial Biofilms.
Abstract Oxidizing agents like hypochlorous acid (HOCl) have antimicrobial activity. We developed an integrated electrochemical scaffold or 'e-scaffold' that delivers a continuous low dose of HOCl aimed at targeting microbial biofilms without exceeding concentrations toxic to humans, as a prototype of a device being developed to treat wound infections in humans. In this work, we tested the device against 33 isolates of bacteria (including isolates with acquired antibiotic resistance) grown as in vitro biofilms, alongside 12 combinations of dual-species in vitro biofilms. Biofilms were grown on the bottoms of 12-we...
Source: Antimicrobial Agents and Chemotherapy - January 4, 2021 Category: Microbiology Authors: Flurin L, Raval YS, Mohamed A, Greenwood-Quaintance KE, Cano EJ, Beyenal H, Patel R Tags: Antimicrob Agents Chemother Source Type: research

Antifungal effect of all-trans retinoic acid against Aspergillus fumigatus in vitro and in a pulmonary aspergillosis in vivo model.
CONCLUSION: Fungistatic efficacy of ATRA alone and synergistically with other antifungal drugs was documented in vitro, likely by inhibiting fungal Hsp90 expression and Hsp90-related genes. ATRA reduced mortality in a model of IPA in vivo Those findings suggest ATRA as suitable fungistatic agent, also to reduce dosage and adverse reaction of classical antifungal drugs, and new therapeutic strategies against IPA and systemic fungal infections. PMID: 33361288 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - December 23, 2020 Category: Microbiology Authors: Campione E, Gaziano R, Doldo E, Marino D, Falconi M, Iacovelli F, Tagliaferri D, Pacello L, Bianchi L, Lanna C, Aurisicchio L, Centofanti F, Di Francesco P, Del Principe I, Del Bufalo F, Locatelli F, Pistoia ES, Marra E, Orlandi A Tags: Antimicrob Agents Chemother Source Type: research

An Updated History of Antimicrobial Agents and Chemotherapy: 2000-2020.
Abstract Since its inaugural issue nearly half a century ago, Antimicrobial Agents and Chemotherapy has served as a premier source for reports on scientific and clinical advances in the field of antimicrobial chemotherapy.…. PMID: 33361289 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - December 23, 2020 Category: Microbiology Authors: Rice LB, Eliopoulos GM Tags: Antimicrob Agents Chemother Source Type: research

Benznidazole in cerebrospinal fluid. a case series of chagas disease meningoencephalitis in hiv positive patients.
ConclusionsWe observed BNZ concentrations in human CSF and plasma. CSF BNZ concentrations were low or non-measurable in all patients, suggesting that usual BNZ doses may be suboptimal in HIV positive patients with T. cruzi meningoencephalitis. While drug-drug and drug-disease interactions may be in part responsible, the factors leading to low CSF BNZ levels remain to be studied in detail. The findings highlight the potential of therapeutic drug monitoring in BNZ treatment, and suggest that use of higher doses may be useful for Chagas disease CNS reactivations. PMID: 33361290 [PubMed - as supplied by publisher] (Source...
Source: Antimicrobial Agents and Chemotherapy - December 23, 2020 Category: Microbiology Authors: Fernández ML, Marson ME, Mastrantonio GE, Corti MA, Fleitas U, Lloveras SC, Lista N, Priarone MM, Domínguez C, Garcia-Bournissen F Tags: Antimicrob Agents Chemother Source Type: research

In vitro selection implicates ROP1 as a resistance gene for an experimental therapeutic benzoquinone acyl hydrazone in Toxoplasma gondii.
Abstract Toxoplasma gondii is a globally distributed apicomplexan parasite and the causative agent of toxoplasmosis in humans. While pharmaceuticals exist to combat acute infection, they can produce serious adverse reactions, demonstrating a need for enhanced therapies. KG8 is a benzoquinone acyl hydrazone chemotype identified from a previous chemical screen for which we previously showed in vitro and in vivo efficacy against T. gondii However, the genetic target and mechanism of action of KG8 remain unknown. To investigate potential targets, we generated resistant T. gondii lines by chemical mutagenesis followed ...
Source: Antimicrobial Agents and Chemotherapy - December 23, 2020 Category: Microbiology Authors: Martens MC, Won MM, Won HI, Schulze TT, Judge AK, Neville AJ, Vennerstrom JL, Davis PH Tags: Antimicrob Agents Chemother Source Type: research

Completion and adverse drug events of latent tuberculosis infection treatment in patients receiving dialysis: predictors and impacts of different regimens in a prospective cohort study.
CONCLUSIONS: For patients on dialysis, 3HP showed a higher rate of completion but also a higher rate of ≥grade 2 ADE than 9H. In addition, DM and PD were risk for ≥grade 2 ADE. Eosinophilia after 2-week treatment might be an alert for severe ADE. PMID: 33361292 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - December 23, 2020 Category: Microbiology Authors: Lin SY, Feng JY, Lee CY, Lin YC, Chou YH, Lin KY, Wei YF, Lin SW, Chang CH, Wang PH, Shu CC, Wang JY, Yu CJ Tags: Antimicrob Agents Chemother Source Type: research

Replacement of S14 protein in ribosomes of zinc-starved mycobacteria reduces spectinamide sensitivity.
We report here that while Mpy binding has no significant effect on Spa sensitivity to the ribosome, replacement of S14c+ with its C- counterpart reduces the binding affinity of the drug by ∼2-fold, causing increased Spa tolerance in Mycobacterium smegmatis and Mycobacterium tuberculosis cells harboring the C- ribosome. The altered interaction between Spa and ribosomes likely results from new contact points for D67 and R83 residues of S14c- with U1138 and C1184 of 16S rRNA helix 34, respectively. Given that M. tuberculosis induces ribosome remodeling during progression from acute to chronic phase of a lung infection, ou...
Source: Antimicrobial Agents and Chemotherapy - December 23, 2020 Category: Microbiology Authors: Li Y, Koripella RK, Sharma MR, Lee RE, Agrawal RK, Ojha AK Tags: Antimicrob Agents Chemother Source Type: research

Dissemination of ESBL-producing Enterobacter cloacae complex from a hospital to the nearby environment in Guadeloupe (French West Indies): ST114 lineage coding for successful IncHI2/ST1 plasmid.
Abstract Wastewater treatment plants are considered hotspots for antibiotic resistance. Most studies have addressed the impact on the aquatic environment, as water is an important source of anthropogenic pollutants. Few investigations have been conducted on terrestrial animals living near treatment ponds. We isolated extended-spectrum beta-lactamase Enterobacter cloacae complex-producing strains from 35 clinical isolates, 29 samples of wastewater, 19 wild animals, and 10 domestic animals living in the hospital sewers and at or near a wastewater treatment plant to study the dissemination of clinically relevant resi...
Source: Antimicrobial Agents and Chemotherapy - December 23, 2020 Category: Microbiology Authors: Pot M, Guyomard-Rabenirina S, Couvin D, Ducat C, Enouf V, Ferdinand S, Gruel G, Malpote E, Talarmin A, Breurec S, Reynaud Y Tags: Antimicrob Agents Chemother Source Type: research

Effects of regulatory network organization and environment on PmrD connector activity and polymyxin resistance in Klebsiella pneumoniae and Escherichia coli.
Abstract Polymyxins are a class of cyclic peptides with antimicrobial activity against Gram-negative bacteria. In Enterobacteriaceae, the PhoQ/PhoP and PmrB/PmrA two-component systems regulate many genes that confer resistance to both polymyxins and host antimicrobial peptides. The activities of these two-component systems are modulated by additional proteins that are conserved across Enterobacteriaceae, such as MgrB, a negative regulator of PhoQ, and PmrD, a "connector" protein that activates PmrB/PmrA in response to PhoQ/PhoP stimulation. Despite the conservation of many protein components of the PhoQ/...
Source: Antimicrobial Agents and Chemotherapy - December 23, 2020 Category: Microbiology Authors: Chen AI, Albicoro FJ, Zhu J, Goulian M Tags: Antimicrob Agents Chemother Source Type: research

Optimization of fluconazole dosing for the prevention and treatment of invasive candidiasis based on the pharmacokinetics of fluconazole in critically-ill patients.
Conclusion: Substantial variability in fluconazole plasma concentrations in critically-ill adults was observed, where the majority of patients were underexposed. Fluconazole Cmin TDM guided dosing can be used to optimize therapy in critically ill patients. PMID: 33361296 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - December 23, 2020 Category: Microbiology Authors: Boonstra JM, Märtson AG, Sandaradura I, Kosterink JG, van der Werf TS, Marriott DJE, Zijlstra JG, Touw DJ, Alffenaar JWC Tags: Antimicrob Agents Chemother Source Type: research

IS26 mediate the acquisition of tigecycline resistance gene cluster tmexCD1-toprJ1 by IncHI1B-FIB plasmids in Klebsiella pneumoniae and Klebsie lla quasipneumoniae from food market sewage.
Abstract Tigecycline and colistin are considered 20 as the final options for the treatment of infections caused by multidrug-resistant (MDR) gram-negative bacteria, especially carbapenem-resistant Enterobacteriaceae (1).…. PMID: 33361297 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - December 23, 2020 Category: Microbiology Authors: Wan M, Gao X, Lv L, Cai Z, Liu JH Tags: Antimicrob Agents Chemother Source Type: research

A Systematic Review of Mutations Associated with Isoniazid Resistance Points to Continuing Evolution and Subsequent Evasion of Molecular Detection, and Potential for Emergence of Multidrug Resistance in Clinical Strains of Mycobacterium tuberculosis.
This article is a systematic review of published articles that reported isoniazid (INH) resistance-conferring mutations between September 2013 and December 2019. The genes katG, inhA, fabG1, and the intergenic region oxyR'-ahpC were considered in this review. Fifty-two articles were included describing 9,306 clinical isolates (5,804 INHR, 3,502 INHS) from 31 countries. The three most frequently mutated loci continue to be katG315 (4,271), inhA-15 (787), and inhA-8 (106). However, the diagnostic value of inhA-8 is far lower than previously thought, only appearing in 25 (0.4%) INHR isolates lacking the first two mutations. W...
Source: Antimicrobial Agents and Chemotherapy - December 23, 2020 Category: Microbiology Authors: Valafar SJ Tags: Antimicrob Agents Chemother Source Type: research

Redox protein OsaR (PA0056) regulates dsbM and the oxidative stress response in Pseudomonas aeruginosa.
In this study, it was found that OsaR can indirectly inhibit transcription of oxyR In addition the gene cluster composed of PA0055, osaR, PA0057 and dsbM was identified, and the associated regulatory mechanisms and functions were elucidated. Our work not only provides a mechanistic understanding of antibiotic tolerance regulation in P. aeruginosa, but also has significant implications for redox regulation in human pathogens in general. PMID: 33361299 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - December 23, 2020 Category: Microbiology Authors: Liu Y, Ma Y, Ma Z, Han X, Qi H, Andersen JB, Xu H, Tolker-Nielsen T, Qiao M Tags: Antimicrob Agents Chemother Source Type: research