Biology subjects

Mezcord, V.

Publications and source records attributed to Mezcord, V..

3 recordsLinked to original sources

bioRxiv2025

Emerging Resistance to Novel -βLactam β-Lactamase Inhibitor Combinations in Klebsiella pneumoniae bearing KPC Variants

BackgroundKlebsiella pneumoniae carbapenemase (KPC) variants, predominantly KPC-2 and KPC-3, are significant global resistance mechanisms. KPC-2 and KPC-3 confer resistance to a broad range of {beta}-lactams, including carbapenems, while remaining susceptible to ceftazidime-avibactam (CZA). Recently, new KPC variants have developed resistance to CZA through mutations, insertions, or deletions in regions such as the {Omega}-loop, 240-loop (237-243 aa), and 270-loop (266-275 aa). This study aimed to investigate the collateral resistance to cefiderocol (FDC) and cefepime/zidebactam (FPZ) among isolates with these mutations. MethodsFifteen clinical isolates of KPC-producing Klebsiella spp. were analyzed, representing 15 distinct variants. Antimicrobial susceptibility testing determined the MICs for CZA, carbapenems, FDC, FPZ, and other antibiotics. Synergy between CZA and FDC was assessed. Whole-genome sequencing (WGS) was used to identify mutations contributing to resistance. ResultsCZA resistance was confirmed in 12 of the 15 KPC variants. Collateral resistance to FDC was observed in eight isolates, with five exhibiting spontaneous resistant subpopulations. Six FDC-resistant strains had mutations in the 270-loop (266-275 aa). Collateral resistance to FPZ was seen in three KPC variants, especially those with mutations in the 270-loop (266-275 aa), though many {Omega}-loop and 240-loop (237-243 aa) mutants remained susceptible. WGS of FDC-resistant subpopulations revealed additional mutations in ompC, rpoC, dksA, and cirA. ConclusionsThis study demonstrates that emerging KPC variants showing resistance to CZA also exhibit resistance to FDC, with collateral resistance to FPZ observed to a lesser extent. Identifying mutations in blaKPC, cirA, and other genes is important to understand resistance mechanisms for effective therapies.

microbiology↗

bioRxiv2024

Hetero-antagonism of avibactam and sulbactam with cefiderocol in carbapenem-resistant Acinetobacter spp.

The emergence of Gram-negative bacteria resistant to multiple antibiotics, particularly carbapenem-resistant (CR) Acinetobacter strains, poses a significant threat globally. Despite efforts to develop new antimicrobial therapies, limited progress has been made, with only two drugs--cefiderocol and sulbactam-durlobactam--showing promise for CR-Acinetobacter infections. Cefiderocol, a siderophore cephalosporin, demonstrates promising efficacy in the treatment of Gram-negative infections. However, resistance to cefiderocol has been reported in A. baumannii. Combination therapies, such as cefiderocol with avibactam or sulbactam, show reduced MICs against cefiderocol-non-susceptible strains with in vivo efficacy, although the outcomes can be complex and species-specific. In the present work, the molecular characterization of spontaneous cefiderocol-resistant variants, a CRAB strain displaying antagonism with sulbactam and an A. lwoffii strain showing antagonism with avibactam, were studied. The results reveal intriguing insights into the underlying mechanisms, including mutations affecting efflux pumps, transcriptional regulators, and iron homeostasis genes. Moreover, gene expression analysis reveals significant alterations in outer membrane proteins, iron homeostasis, and {beta}-lactamases, suggesting adaptive responses to selective pressure. Understanding these mechanisms is crucial for optimizing treatment strategies and preventing adverse clinical outcomes. This study highlights the importance of preemptively assessing drug synergies to navigate the challenges posed by antimicrobial resistance in CR-Acinetobacter infections.

microbiology↗

bioRxiv2022

The Iron Content of Human Serum Albumin Modulates the Susceptibility of Acinetobacter baumannii to Cefiderocol

Mortality rates of patients infected with Acinetobacter baumannii treated with cefiderocol (CFDC) were not as favorable as the best available treatment for pulmonary and bloodstream infections. Previous studies showed that the presence of human serum albumin (HSA) or HSA-containing fluids like human pleural fluid (HPF) or human serum (HS) in the growth medium is correlated with a decrease in the expression of genes associated with high-efficiency iron uptake systems. These observations may explain the less-than-ideal performance of CFDC in pulmonary and bloodstream infections because ferric siderophore transporters enhance penetration of CFDC into the cells cytosol. Removal of HSA from HPF or HS resulted in a reduction of the minimal inhibitory concentration of CFDC. Concomitant with these results, there was an enhancement of the expression of genes associated with high-efficiency iron uptake systems. In addition to inducing modifications in iron-uptake gene expression, removal of HSA also decreased the expression of {beta}-lactam resistance genes. Taken together, these observations indicate that environmental HSA has a role in the expression levels of selected A. baumannii. Furthermore, removal of iron from HSA had the same effect as removal of HSA on the expression of genes associated with high-efficiency iron uptake systems, suggesting that at least one of the mechanisms by which HSA regulates the expression of selected genes is through acting as an iron supplier. IMPORTANCECefiderocol (CFDC) is a new antibiotic that combines its major bactericidal activity, i.e., inhibition of the Gram-negative bacterial cell wall synthesis, with a first in its class mechanism of cell penetration. The siderophore-like moiety facilitates entry through receptors that recognize ferric-siderophore complexes. Recent trials showed that treating pulmonary and bloodstream Acinetobacter baumannii infections with CFDC did not result in the same outcomes as treating other pathogens. Our studies indicated that exposure to human fluids that contain human serum albumin (HSA) increases the MIC values of CFDC. Results described in this work show that HSA is responsible for a reduction in susceptibility of A. baumannii to CFDC. Furthermore, the presence of HSA in the milieu produces a reduction in levels of expression of proteins associated with high-affinity iron uptake systems and enhanced expression of {beta}-lactam resistance-associated genes. Deferration of HSA was accompanied by a loss of the ability to modify these genes expression levels. These results indicate that the microbiological activity of CFDC towards A. baumannii is attenuated in the presence of HSA-containing fluids. This unique insight opens up new avenues of investigation. Understanding this phenomenons molecular mechanism will help define methodologies to increase treatment efficiency.

microbiology↗