Antimicrobial Agents and Chemotherapy

The emergence of multidrug-resistant Candidozyma auris has created an urgent need for antifungals with novel mechanisms of action. We screened 121 nucleoside and nucleobase derivatives against C. auris and other clinically relevant Candida species to identify effective antimetabolite scaffolds. Among all compounds tested, only the C-5-fluorinated nucleosides 5-fluorouridine (5-FU) and 5-fluorocytidine exhibited potent antifungal activity. 5-FU demonstrated consistently low minimum inhibitory...

Clostridioides difficile infection (CDI) remains a major cause of healthcare-associated diarrhea worldwide, and is classified as an urgent public health threat by the Centers for Disease Control and Prevention. Current frontline therapies, including vancomycin and fidaxomicin, are associated with disruption of the intestinal microbiota, recurrence, and emerging reduced susceptibility, underscoring the need for additional therapeutic strategies. Using a drug-repurposing approach, we identified...

NDM-14-producing Klebsiella pneumoniae ST147 has recently emerged as a high-risk clone in Europe, but its local dissemination dynamics remain poorly defined. We investigated a 6-month outbreak across three hospitals within a regional healthcare network in Lombardy, Northern Italy. Among 32 NDM-producing K. pneumoniae, isolated between December 2024 and May 2025, 19 belonged to ST147, including one NDM-1 producer and 18 carrying NDM-14 or its A233V variant NDM-61. Phylodynamic analysis of the...

No abstract

Metformin is under investigation as adjunctive host-directed therapy for tuberculosis (TB), which might interact with first-line TB treatment. We used population pharmacokinetic modeling to assess whether metformin alters first-line TB-drug pharmacokinetics in HIV/TB-coinfected adults without diabetes. Rifampicin, isoniazid, and pyrazinamide pharmacokinetics were investigated in participants from a randomized clinical trial of adjunctive metformin (500 mg twice daily to week 12) in adults...

Hypermutation-driven evolution is a major contributor to antibiotic resistance in some bacterial pathogens, but its role in Klebsiella pneumoniae remains poorly defined. We analyzed 11 KPC-producing ST258 K. pneumoniae isolates collected serially over ~4 years from a host with persistent colonization and recurrent infections. After >3 years, isolates acquired ceftazidime-avibactam (CZA) resistance with restored carbapenem susceptibility, coinciding with emergence of a V76G substitution in MutH,...

Phage therapy and phage-antibiotic combinations are promising strategies against multidrug-resistant pathogens like carbapenem-resistant Klebsiella pneumoniae (CRKP). However, the mechanisms underlying phage resistance and the molecular basis of the rational design of phage-antibiotic combinations require further investigation. Using genome-wide transposon screening, CRISPR-Cas9 knockout, and plasmid complementation in a clinical ST11-KL64 CRKP strain, we investigated susceptibility determinants...

Early during the COVID-19 pandemic, non-human primate (NHP) infection models emerged as highly useful tools for preclinical screening of antiviral drugs. However, it is uncertain whether NHP models can be used to precisely inform optimal dosing in humans. We previously established and validated mathematical models, which were fit to SARS-CoV-2 viral loads from human clinical trials. These models identified that plasma drug concentrations required to inhibit viral replication by 50% in humans (in...

Klebsiella pneumoniae ST383 has emerged as a high-risk clone, characterized by carbapenem resistance and increasing detection of hypervirulence determinants. We describe a phylogenetically distinct ST383 sub-lineage in Lebanon, defined by the acquisition of ICEKp5, which carries the yersiniabactin locus. Three ST383 K. pneumoniae clinical isolates (LBN_CAKp91, LBN_CTKp3, and LBN_CTKp11) recovered from a Lebanese medical center were subjected to whole-genome sequencing. Comparative genomic...

This study aimed to establish epidemiological cutoff values (ECVs) for amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole against Talaromyces marneffei (T. marneffei) using the CLSI broth microdilution method. Antifungal susceptibility testing of 207 T. marneffei isolates was performed independently at five laboratories across China according to CLSI M27-A4 guidelines. Minimum inhibitory concentration (MIC) distributions were analyzed using ECOFFinder...

Invasive fungal infections (IFIs) remain a major global health threat due to limited therapeutic options and rising azole resistance. NT-a9 is a novel triazole antifungal with potent activity against Candida and Cryptococcus species via strong inhibition of ergosterol biosynthesis. In vitro, NT-a9 exhibited potent and sustained antifungal activity against clinical isolates, with superior potency compared to fluconazole (FLC). It also displayed a prolonged post-antifungal effect (PAFE) against...

Eliminating the latent HIV-1 reservoir remains a major barrier to achieving a functional cure. The "block-and-lock" strategy aims to enforce durable transcriptional silencing of proviruses, thereby preventing viral rebound upon interruption of antiretroviral therapy. However, the molecular mechanisms governing stable latency remain incompletely understood. Here, we identify protein kinase C (PKC)-dependent phosphorylation of STAT1 and STAT3 at serine 727 as a previously unrecognized regulatory...

Clostridioides difficile infection (CDI) has limited antibiotic treatment options, with fidaxomicin being the guideline-preferred antibiotic. C. E. Kaple, S. N. Redmond, J. L. Cadum, B. Hausman, et al. (Antimicrob Agents Chemother 0:e00130-26, 2026, https://doi.org/10.1128/aac.00130-26) describe a case of clinical failure in an elderly patient with CDI treated with a pulsed-taper fidaxomicin regimen, in which the MIC increased from 0.05 μg/mL at baseline to 32 μg/mL in isolates recovered during...

Zoliflodacin is a first-in-class spiropyrimidinetrione, oral, single-dose antibacterial recently approved by the US FDA for treatment of uncomplicated urogenital gonorrhea. Isolates of Neisseria gonorrhoeae (n = 322) collected in the United States in 2020-2022 by the Centers for Disease Control and Prevention, as well as two ceftriaxone-resistant isolates, were tested for susceptibility to zoliflodacin. All isolates were susceptible to zoliflodacin with MIC(50/90) values of 0.12 µg/mL....

Programmed -1 ribosomal frameshifting (-1 PRF) is a translational recoding mechanism used by many RNA viruses to regulate the expression of viral replication proteins. In coronaviruses, including SARS-CoV-2, -1 PRF is controlled by a conserved frameshift stimulation element containing a three-stemmed RNA pseudoknot located downstream of a slippery sequence. Studies have shown that conformational dynamics, mechanical stability, and structural variability of the pseudoknot influence ribosome...