Imipenem/Relebactam Resistance in Clinical Isolates of Extensively Drug Resistant Pseudomonas aeruginosa: Inhibitor-Resistant β-Lactamases and Their Increasing Importance
| Autor: | Andrea M. Hujer, Christopher R. Bethel, Magdalena A. Taracila, Steven H. Marshall, Laura J. Rojas, Marisa L. Winkler, Ronald E. Painter, T. Nicholas Domitrovic, Richard R. Watkins, Ayman M. Abdelhamed, Roshan D’Souza, Andrew R. Mack, Richard C. White, Thomas Clarke, Derrick E. Fouts, Michael R. Jacobs, Katherine Young, Robert A. Bonomo |
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| Rok vydání: | 2022 |
| Předmět: |
Pharmacology
Porins Microbial Sensitivity Tests biochemical phenomena metabolism and nutrition bacterial infections and mycoses United States beta-Lactamases Anti-Bacterial Agents Drug Combinations Imipenem Infectious Diseases Mechanisms of Resistance Pseudomonas aeruginosa polycyclic compounds bacteria Humans Pharmacology (medical) Pseudomonas Infections Amino Acids Azabicyclo Compounds |
| Zdroj: | Antimicrob Agents Chemother |
| ISSN: | 1098-6596 |
| Popis: | Multidrug-resistant (MDR) Pseudomonas aeruginosa infections are a major clinical challenge. Many isolates are carbapenem resistant, which severely limits treatment options; thus, novel therapeutic combinations, such as imipenem-relebactam (IMI/REL), ceftazidime-avibactam (CAZ/AVI), ceftolozane-tazobactam (TOL/TAZO), and meropenem-vaborbactam (MEM/VAB) were developed. Here, we studied two extensively drug-resistant (XDR) P. aeruginosa isolates, collected in the United States and Mexico, that demonstrated resistance to IMI/REL. Whole-genome sequencing (WGS) showed that both isolates contained acquired GES β-lactamases, intrinsic PDC and OXA β-lactamases, and disruptions in the genes encoding the OprD porin, thereby inhibiting uptake of carbapenems. In one isolate (ST17), the entire C terminus of OprD deviated from the expected amino acid sequence after amino acid G388. In the other (ST309), the entire oprD gene was interrupted by an ISPa1328 insertion element after amino acid D43, rendering this porin nonfunctional. The poor inhibition by REL of the GES β-lactamases (GES-2, -19, and -20; apparent K(i) of 19 ± 2 μM, 23 ± 2 μM, and 21 ± 2 μM, respectively) within the isolates also contributed to the observed IMI/REL-resistant phenotype. Modeling of REL binding to the active site of GES-20 suggested that the acylated REL is positioned in an unstable conformation as a result of a constrained Ω-loop. |
| Databáze: | OpenAIRE |
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