Antimicrobial Agents and Chemotherapy

The carbapenemases Klebsiella pneumoniae carbapenemase (KPC) and New Delhi metallo-β-lactamase (NDM) are the most widespread determinants of carbapenem resistance in Klebsiella pneumoniae. Whereas KPC is a soluble periplasmic serine-β-lactamase, NDM is a membrane-anchored metallo-β-lactamase (MBL), a feature that promotes its incorporation into outer membrane vesicles (OMVs). OMVs are naturally released nanoparticles that deliver diverse bioactive cargo, including enzymes, virulence factors, and...

Pseudomonas aeruginosa presents a significant challenge in both clinical and antibiotic discovery settings due to the low permeability of its cell envelope. Efflux pumps acting synergistically with the permeability barrier of the outer membrane provide efficient protection against various antibacterial agents. Among 12 P. aeruginosa efflux pumps from the resistance-nodulation-division (RND) superfamily, the MexEF-OprN efflux system-and its transporter component MexF-remains relatively...

Approximately 20% of human cancers have been attributed to virus infections, including Kaposi's sarcoma-associated herpesvirus (KSHV), which can cause several human cancers arising in immunocompromised patients. KSHV can also establish lifelong infection in immunocompetent individuals. The prevalence of KSHV infection is high in HIV-endemic regions, such as sub-Saharan Africa, as well as in certain subpopulations, including men who have sex with men (MSM) and organ transplant recipients....

Antimicrobial options for Mycoplasma genitalium are limited. Our prior study found a 14-day regimen of minocycline and metronidazole (minocycline + metronidazole) achieved microbial cure in 76.7% (n = 56/73, 95% confidence interval [95% CI]: 65.4%-85.8%) of macrolide-resistant infections, with an efficacy of 90.3% (n = 28/31, 95% CI: 74.2%-98.0%) if preceded by 7 days of doxycycline. We aimed to evaluate the efficacy and tolerability of sequential doxycycline and 14 days of minocycline +...

SPR720 is an aminobenzimidazole prodrug that is rapidly converted in vivo to SPR719, an inhibitor of the DNA gyrase B ATPase subunit in mycobacteria. SPR719 demonstrates potent in vitro activity against clinically relevant Mycobacterium avium complex (MAC) species. This study evaluated the pharmacokinetics (PK), safety, and tolerability of SPR720, azithromycin, and ethambutol administered alone and in combination in healthy adults. Participants were assigned to one of five groups and received...

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Ulonivirine is a non-nucleoside reverse transcriptase inhibitor in development as an oral, once-weekly treatment for HIV-1 in combination with investigational islatravir. The effect of ulonivirine on the pharmacokinetics of an oral contraceptive, levonorgestrel (LNG)/ethinyl estradiol (EE) was evaluated in females without HIV. In this Phase 1 study (MK-8507-009), postmenopausal or oophorectomized females received a single dose of LNG/EE (0.1 mg/0.02 mg), followed by a 5-day washout period....

DNA methyltransferases in Helicobacter pylori regulate processes beyond genome defense, but whether they directly modulate β-lactam susceptibility has remained unclear. Here, we identify the conserved CATG methyltransferase M.HpyAI (HP1208) as a key determinant of cell wall homeostasis and antibiotic response. Deletion of hp1208 in strain 26695 caused a marked increase in β-lactam susceptibility and impaired growth under osmotic stress, consistent with defective peptidoglycan biogenesis....

Staphylococcus aureus remains one of the world's deadliest pathogens. OSUAB-0284 (284) is a novel, small-molecule anti-staphylococcal agent targeting bacterial type II topoisomerases. 284 inhibited supercoiling by DNA gyrase and decatenation by topoisomerase IV with similar (balanced) potency (IC(50) values of 0.80 and 0.15 μM, respectively) and promoted the accumulation of single-strand DNA breaks mediated by DNA gyrase and topoisomerase IV. Cryo-electron microscopy of 284 in ternary complex...

Carbapenemase-producing Enterobacterales represent a growing global threat due to their extensive antimicrobial resistance and rapid dissemination. This study characterized the phenotypic and genomic features of Escherichia coli and Klebsiella pneumoniae isolates collected between 2020 and 2022 from four healthcare institutions in Lima, Peru. A total of 320 non-redundant isolates (61 E. coli and 259 K. pneumoniae) were analyzed through antimicrobial susceptibility testing, polymerase chain...

Rifampicin-resistant (RIF-R) and methicillin-resistant Staphylococcus epidermidis (MRSE) pose a significant challenge in managing implant-associated infections (IAIs). However, the functional consequences of rpoB mutations leading to RIF resistance remain poorly characterized, particularly their impact on bacterial fitness and treatment response. We analyzed clinical RIF-R and RIF-susceptible (RIF-S) MRSE isolates from a single-center IAI cohort. RIF-R strains showed delayed exponential growth...

Klebsiella pneumoniae is an important cause of human infections and is often resistant to multiple antibiotics. Most infections occur in individuals with co-morbidities and/or those who have risk factors for infection. Although progress has been made, new therapeutics and preventive measures are needed. To that end, we developed a mouse model of severe/fatal K. pneumoniae infection (intraperitoneal inoculation that leads to bacteremia) to evaluate strain virulence and test protection conferred...

Oral ceftibuten and tebipenem, alone or combined with avibactam, ledaborbactam, or xeruborbactam, were evaluated against recombinant Escherichia coli producing 57 acquired β-lactamases. Tebipenem showed greater intrinsic activity than ceftibuten against extended-spectrum β-lactamase (ESBL) and AmpC producers. Whereas avibactam and ledaborbactam remained inactive against metallo-β-lactamases, xeruborbactam restored activity against most class B producers. Tebipenem-xeruborbactam demonstrated the...

Plasmodium falciparum resistance to current first-line treatments is threatening at-risk populations and underscores the urgent need for novel therapeutic targets and drugs. P. falciparum pyruvate kinases I and II are two essential enzymes with distinct roles and subcellular localizations within the parasite. PfPyrKI is cytosolic, while PfPyrKII is found in the apicoplast, a specific organelle of Apicomplexa, where it is required for the production of (d)NTPs essential for apicoplast...