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Bactericidal and sterilizing activity of sudapyridine-clofazimine-TB47 combined with linezolid or pyrazinamide in a murine model of tuberculosis
Antimicrob Agents Chemother. 2024 May 1:e0012424. doi: 10.1128/aac.00124-24. Online ahead of print.ABSTRACTAs an obligate aerobe, Mycobacterium tuberculosis relies on its branched electron transport chain (ETC) for energy production through oxidative phosphorylation. Regimens targeting ETC exhibit promising potential to enhance bactericidal activity against M. tuberculosis and hold the prospect of shortening treatment duration. Our previous research demonstrated that the bacteriostatic drug candidate TB47 (T) inhibited the growth of M. tuberculosis by targeting the cytochrome bc1 complex and exhibited synergistic activity ...
Source: Antimicrobial Agents and Chemotherapy - May 1, 2024 Category: Microbiology Authors: Wei Yu Yanan Ju Xingli Han Xirong Tian Jie Ding Shuai Wang H M Adnan Hameed Yamin Gao Lei Li Yongguo Li Nanshan Zhong Tianyu Zhang Source Type: research

The Spx stress regulator confers high-level β-lactam resistance and decreases susceptibility to last-line antibiotics in methicillin-resistant Staphylococcus aureus 
Antimicrob Agents Chemother. 2024 May 1:e0033524. doi: 10.1128/aac.00335-24. Online ahead of print.ABSTRACTInfections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a leading cause of mortality worldwide. MRSA has acquired resistance to next-generation β-lactam antibiotics through the horizontal acquisition of the mecA resistance gene. Development of high resistance is, however, often associated with additional mutations in a set of chromosomal core genes, known as potentiators, which, through poorly described mechanisms, enhance resistance. The yjbH gene was recently identified as a hot spot for adaptiv...
Source: Antimicrobial Agents and Chemotherapy - May 1, 2024 Category: Microbiology Authors: Tobias Krogh Nielsen Ida Birkj ær Petersen Lijuan Xu Maria Disen Barbuti Viktor Mebus Anni Justh Abdulelah Ahmed Alqarzaee Nicolas Jacques C écile Oury Vinai Thomas Morten Kjos Camilla Henriksen Dorte Frees Source Type: research

Insights into the activity of cefiderocol against PER-2 producing Enterobacterales
In this study, we explored the stability of cefiderocol (FDC) against PER-2 β-lactamase to gain insights into structure activity relationships (SAR) of this synthetic siderophore-conjugated antibiotic. Herein, we show that the MICs of FDC for PER-2 producing isolates and transformants ranged between 0.125 and 64 µg/mL; diazabicyclooctanes (DBOs) reduced the MIC values. In PER-2 mutants, MIC values decreased up to 10-12 dilutions in agreement with previous observations especially in the case of Arg220 substitutions. Catalytic efficiency for PER-2 was 0.072 µM-1 s-1, comparable with PER-1 (0.046 µM-1 s-1) and NDM-1 (0.06...
Source: Antimicrobial Agents and Chemotherapy - May 1, 2024 Category: Microbiology Authors: Melina Ruggiero Ivan Brice ño Muñoz Gabriel Gutkind Andrea M Hujer Robert A Bonomo Pablo Power Source Type: research

A pairwise approach to revitalize β-lactams for the treatment of TB
Antimicrob Agents Chemother. 2024 May 1:e0003424. doi: 10.1128/aac.00034-24. Online ahead of print.ABSTRACTThe dual β-lactam approach has been successfully applied to overcome target redundancy in nontuberculous mycobacteria. Surprisingly, this approach has not been leveraged for Mycobacterium tuberculosis, despite the high conservation of peptidoglycan synthesis. Through a comprehensive screen of oral β-lactam pairs, we have discovered that cefuroxime strongly potentiates the bactericidal activity of tebipenem and sulopenem-advanced clinical candidates-and amoxicillin, at concentrations achieved clinically. β-lactam pa...
Source: Antimicrobial Agents and Chemotherapy - May 1, 2024 Category: Microbiology Authors: Dereje A Negatu Wassihun Wedajo Aragaw V éronique Dartois Thomas Dick Source Type: research

Development of rabbit models of ventilator-associated bacterial pneumonia produced by carbapenem-resistant Pseudomonas aeruginosa 
Antimicrob Agents Chemother. 2024 Apr 30:e0020524. doi: 10.1128/aac.00205-24. Online ahead of print.ABSTRACTVentilator-associated bacterial pneumonia (VABP) is among the most intractable of carbapenem-resistant Gram-negative bacterial infections. New antimicrobial agents are critically needed for the treatment of VABP. However, current conventionally used animal model systems are inadequate to meet this challenge. We, therefore, developed rabbit models of VABP caused by carbapenem-resistant Pseudomonas aeruginosa. Persistently neutropenic New Zealand White rabbits were used throughout the study. The early-phase intubated m...
Source: Antimicrobial Agents and Chemotherapy - April 30, 2024 Category: Microbiology Authors: Vidmantas Petraitis Ruta Petraitiene Povilas Kavaliauskas Ethan Naing Andrew Garcia Vilma Zigmantaite Ramune Grigaleviciute Audrius Kucinskas Alius Pockevicius Rimantas Stakauskas Thomas J Walsh Source Type: research

Efficacy of an oral lipid nanocrystal formulation of amphotericin B (MAT2203) in the neutropenic mouse model of pulmonary mucormycosis
Antimicrob Agents Chemother. 2024 Apr 30:e0154023. doi: 10.1128/aac.01540-23. Online ahead of print.ABSTRACTInvasive mucormycosis (IM) is associated with high mortality and morbidity. MAT2203 is an orally administered lipid nanocrystal formulation of amphotericin B, which has been shown to be safe and effective against other fungal infections. We sought to compare the efficacy of MAT2203 to liposomal amphotericin B (LAMB) treatment in a neutropenic mouse model of IM due to Rhizopus arrhizus var. delemar or Mucor circinelloides f. jenssenii DI15-131. In R. arrhizus var. delemar-infected mice, 15 mg/kg of MAT2203 qd was as e...
Source: Antimicrobial Agents and Chemotherapy - April 30, 2024 Category: Microbiology Authors: Yiyou Gu Teclegiorgis Gebremariam Sondus Alkhazraji Eman Youssef Sabrina El-Gamal Theresa Matkovits Jenel Cobb Raphael Mannino Ashraf S Ibrahim Source Type: research

The nucleoside analog 4'-fluorouridine suppresses the replication of multiple enteroviruses by targeting 3D polymerase
In this study, we found that 4'-fluorouridine (4'-FlU), a nucleoside analog with low cytotoxicity, exhibited broad-spectrum activity against infections of multiple enteroviruses with EC50 values at low micromolar levels, including coxsackievirus A10 (CV-A10), CV-A16, CV-A6, CV-A7, CV-B3, enterovirus A71 (EV-A71), EV-A89, EV-D68, and echovirus 6. With further investigation, the results indicated that 4'-FlU directly interacted with the RNA-dependent RNA polymerase of enterovirus, the 3D pol, and impaired the polymerase activity of 3D pol, hence inhibiting viral RNA synthesis and significantly suppressing viral replication. ...
Source: Antimicrobial Agents and Chemotherapy - April 30, 2024 Category: Microbiology Authors: Yongkang Chen Xiaohong Li Fengyang Han Beihong Ji Yuan Li Jingjing Yan Min Wang Jun Fan Shuye Zhang Lu Lu Peng Zou Source Type: research

Doxycycline, levofloxacin, and moxifloxacin are superior to ciprofloxacin in treating anthrax meningitis in rabbits and NHP
Antimicrob Agents Chemother. 2024 Apr 30:e0161023. doi: 10.1128/aac.01610-23. Online ahead of print.ABSTRACTEfficient treatment of anthrax-related meningitis in patients poses a significant therapeutic challenge. Previously, we demonstrated in our anthrax meningitis rabbit model that ciprofloxacin treatment is ineffective with most of the treated animals succumbing to the infection. Herein we tested the efficacy of doxycycline in our rabbit model and found it highly effective. Since all of our findings are based on a rabbit model, we test the efficacy of ciprofloxacin or doxycycline in a specific central nervous system (CN...
Source: Antimicrobial Agents and Chemotherapy - April 30, 2024 Category: Microbiology Authors: Amir Ben-Shmuel Itai Glinert Assa Sittner Elad Bar-David Josef Schlomovitz Haim Levy Shay Weiss Source Type: research

 In vitro activity of gepotidacin and comparator antimicrobials against isolates of nontuberculous mycobacteria (NTM)
Antimicrob Agents Chemother. 2024 Apr 24:e0168423. doi: 10.1128/aac.01684-23. Online ahead of print.ABSTRACTNovel antimicrobials are needed to treat rising nontuberculous mycobacteria (NTM) infections. Using standard broth microdilution methods, 68 NTM isolates were tested against gepotidacin, a new, first-in-class, oral triazaacenaphthylene bacterial topoisomerase inhibitor. MICs varied (0.25 to >64 µg/mL) with the lowest being M. fortuitum complex (0.25-8 µg/mL), M. mucogenicum complex (1-2 µg/mL), M. kansasii (0.25-8 µg/mL), and M. marinum (4-16 µg/mL). Testing greater numbers of some species is suggested to bet...
Source: Antimicrobial Agents and Chemotherapy - April 24, 2024 Category: Microbiology Authors: Barbara A Brown-Elliott Georgie Bush M Dolores Hughes Eliana Rodriguez Chase A Weikel Sharon B Min Richard J Wallace Source Type: research

Loureirin A is a narrow-spectrum antimicrobial agent against Helicobacter pylori 
In this study, loureirin A (LrA), a traditional Chinese medicine monomer extracted from Sanguis Draconis flavones, was found to possess specific antibacterial activity against H. pylori without the bacteria displaying a tendency to develop resistance in vitro. LrA demonstrated a synergistic or additive effect when combined with omeprazole (a proton pump inhibitor) against H. pylori. The combination of LrA and omeprazole showed promising anti-H. pylori potential, exhibiting notable in vivo efficacy comparable to standard triple therapy in mouse models infected with both drug-sensitive and drug-resistant H. pylori strains. M...
Source: Antimicrobial Agents and Chemotherapy - April 24, 2024 Category: Microbiology Authors: Qian Tong Chengqiang Yin Xudong Hang Yuefan Bai Chongwen Zhang Jingcheng Xu Yan Huang Yixin Ge Tianyu Chen Liping Zeng Jia Jia Hongkai Bi Source Type: research

How to use meropenem in pediatric patients undergoing CKRT? Integrated meropenem pharmacokinetic model for critically ill children
Antimicrob Agents Chemother. 2024 Apr 24:e0172923. doi: 10.1128/aac.01729-23. Online ahead of print.ABSTRACTStandard dosing could fail to achieve adequate systemic concentrations in ICU children or may lead to toxicity in children with acute kidney injury. The population pharmacokinetic analysis was used to simultaneously analyze all available data (plasma, prefilter, postfilter, effluent, and urine concentrations) and provide the pharmacokinetic characteristics of meropenem. The probability of target fT > MIC attainment, avoiding toxic levels, during the entire dosing interval was estimated by simulation of different i...
Source: Antimicrobial Agents and Chemotherapy - April 24, 2024 Category: Microbiology Authors: Laura Butrague ño-Laiseca I ñaki F Troconiz Santiago Grau Nuria Campillo Bel én Padilla Sarah Nicole Fern ández Mar ía Slöcker Laura Herrera Mar ía José Santiago Source Type: research