Antimicrobial Agents and Chemotherapy最新文献

{"title":"Antibiotic synergy against <i>Staphylococcus aureus</i>: a systematic review and meta-analysis.","authors":"Madeline Mellett, Alexander Lawandi, Chelsea Caya, Todd C Lee, Ahmed Babiker, Jesse Papenburg, Cedric P Yansouni, Matthew P Cheng","doi":"10.1128/aac.01199-24","DOIUrl":"https://doi.org/10.1128/aac.01199-24","url":null,"abstract":"<p><p>Antimicrobial combinations have been extensively evaluated <i>in vitro</i> to identify synergistic combinations for clinical use. Despite the available literature, no studies comprehensively summarize the findings for antimicrobial combinations against <i>Staphylococcus aureus</i>. We performed a systematic review to identify synergistic combinations that may be beneficial for clinical use against <i>S. aureus</i>. The PubMed, Cochrane, and Web of Science databases were queried from inception to February 2024 for studies of <i>in vitro</i> assays evaluating two antimicrobials in combination against isolates of <i>S. aureus</i>. Studies were included if they used common methods to determine synergy including time-kill assays, checkerboard assays, or the combined gradient diffusion method. The proportion of isolates for which synergy was identified was compared for different antimicrobial combinations. Two hundred sixty-five studies were included for analysis. One hundred forty-two studies evaluated synergy against methicillin-resistant <i>S. aureus</i> (MRSA), 31 against methicillin-susceptible <i>S. aureus</i> (MSSA), and 92 assessed synergy against both MRSA and MSSA, or did not define the methicillin susceptibility profile of the isolates studied. Time-kill assays (<i>n</i> = 176) and checkerboard assays (<i>n</i> = 158) were the most frequently used methods, with few studies evaluating synergy using the combined gradient diffusion method (<i>n</i> = 13). The proportion of synergy varied based on the antimicrobial combination and isolate being evaluated. Antimicrobial synergy has been extensively studied for <i>S. aureus</i>, with combinations of glycopeptides and cephalosporins being studied most frequently. Future evaluations of synergy for <i>S. aureus</i> should focus on antimicrobial combinations with strong rationales and robust potential for clinical use.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0119924"},"PeriodicalIF":4.1,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of respiratory tract mimicking media on antifungal susceptibility testing.","authors":"Roya Vahedi-Shahandashti, Isabella Hofer, Hollie Leighton, Joanne L Fothergill, Daniel R Neill, Cornelia Lass-Flörl","doi":"10.1128/aac.00225-25","DOIUrl":"https://doi.org/10.1128/aac.00225-25","url":null,"abstract":"<p><p>The rise in antifungal resistance and changing epidemiology underscores the need to improve antifungal susceptibility testing. This study tested the standard medium RPMI₁₆₄₀ and healthy lung and sinus media against <i>Aspergillus</i>, <i>Mucor</i>, and <i>Candida</i> species. <i>Candida</i> showed greater variability in minimum inhibitory concentrations (MICs) compared with molds, with higher MICs in respiratory tract-mimicking media than in RPMI₁₆₄₀. <i>Aspergillus terreus</i> was the most affected mold, showing higher MICs for certain antifungals in these media.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0022525"},"PeriodicalIF":4.1,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel C5α-substituted carbapenems enhance <i>Mycobacterium abscessus</i> killing via selective target binding and reduced hydrolysis by Bla_Mab.","authors":"Eunjeong Shin, Magdalena A Taracila, Pojun Quan, Md Mahbub Kabir Khan, Jonathan Cox, Diya Patel, Khalid M Dousa, Aetan Parmar, Mary Nantongo, David C Nguyen, Eric J Rubin, Steven M Holland, Barry N Kreiswirth, John D Buynak, Robert A Bonomo","doi":"10.1128/aac.00170-25","DOIUrl":"https://doi.org/10.1128/aac.00170-25","url":null,"abstract":"<p><p><i>Mycobacterium abscessus</i> (<i>Mab</i>) poses significant clinical challenges and underscores the urgent need for safer and more effective treatments, including β-lactams. Among currently available carbapenems, imipenem is widely used to treat <i>Mab</i> infections by combining with other antibiotics. Commercial carbapenems share a common scaffold with C2 modifications, whereas this study focuses on novel carbapenem candidates with C5α modifications. We evaluated their antibacterial activity against <i>Mab</i> ATCC 19977 and clinical isolates, as well as their acylation of peptidoglycan target receptors (L,D-transpeptidases [LDTs] and penicillin-binding proteins [PBPs]) and the β-lactamase enzyme Bla_Mab. <i>In vitro</i> studies of two C5α-modified carbapenems, JDB/NA-1-157 and JDB/NA-1-208, revealed distinct antibacterial effects. JDB/NA-1-157 demonstrated potent bacterial killing with low minimum inhibitory concentrations (MICs; 0.125-8 mg/L) and near-complete eradication within 5 days, surpassing the efficacy of the standard-of-care regimen (amikacin + clarithromycin + imipenem). In contrast, JDB/NA-1-208 exhibited poor bacterial killing, with high MICs (16-256 mg/L) and limited efficacy in time-kill studies. However, JDB/NA-1-208 showed synergistic killing when combined with other β-lactams. Mechanistically, JDB/NA-1-208 is not a substrate for Bla_Mab, while JDB/NA-1-157 is, albeit with low catalytic efficiency. This is supported by the observation that the addition of avibactam did not enhance synergy with JDB/NA-1-157. The substantial bacterial killing effect of JDB/NA-1-157 is attributed to its high binding affinity for PBP-B, PBP-lipo, PonA2, D,D-carboxypeptidase, and LDT1-2. These findings highlight the potential of novel C5α-modified carbapenems, particularly JDB/NA-1-157, as promising therapeutic candidates for <i>Mab</i> infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0017025"},"PeriodicalIF":4.1,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteogenomic analysis demonstrates increased <i>bla</i>_OXA-48 copy numbers and OmpK36 loss as contributors to carbapenem resistance in <i>Klebsiella pneumoniae</i>.","authors":"Lisa M Meekes, Astrid P Heikema, Manuela Tompa, Ana L Astorga Alsina, Saskia D Hiltemann, Andrew P Stubbs, Lennard J M Dekker, Dimard E Foudraine, Nikolaos Strepis, Johann D D Pitout, Gisele Peirano, C H W Klaassen, W H F Goessens","doi":"10.1128/aac.00107-25","DOIUrl":"https://doi.org/10.1128/aac.00107-25","url":null,"abstract":"<p><p>Antimicrobial resistance arises from complex genetic and regulatory changes, including single mutations, gene acquisitions, or cumulative effects. Advancements in genomics and proteomics facilitate a more comprehensive understanding of the mechanisms behind antimicrobial resistance. In this study, 74 clinically obtained <i>Klebsiella pneumoniae</i> isolates with increased meropenem and/or imipenem MICs were characterized by broth microdilution and PCR to check for the presence of carbapenemase genes. Subsequently, a representative subset of 15 isolates was selected for whole-genome sequencing (WGS) by Illumina and Nanopore sequencing, and proteomic analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to investigate the mechanisms underlying the differences in carbapenem susceptibility of <i>Klebsiella pneumoniae</i> isolates. Identical techniques were applied to characterize four mutants obtained after sequential meropenem exposure. We demonstrated that in clinically obtained isolates, increased copy numbers of <i>bla</i>_OXA-48-containing plasmids, combined with OmpK36 loss, contributed to high carbapenem MICs without the involvement of OmpK35 or other porins or efflux systems. In the meropenem-exposed mutants, increased copy numbers of <i>bla</i>_CTX-M-15 or <i>bla</i>_OXA-48-containing plasmids, combined with OmpK36 loss, were demonstrated. The OmpK36 loss resulted from the insertion of IS1 transposable elements or partial deletion of the <i>ompK36</i> gene. Additionally, we identified two mutations, C59A and C58A, in the DNA coding the copA antisense RNA of IncFII plasmids and multiple mutations of an IncR plasmid, associated with increased plasmid copy numbers. This study demonstrates that by combining WGS and LC-MS/MS, the effect of genomic changes on protein expression related to antibiotic resistance and the mechanisms behind antibiotic resistance can be elucidated.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0010725"},"PeriodicalIF":4.1,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"D-alanine synthesis and exogenous alanine affect the antimicrobial susceptibility of <i>Staphylococcus aureus</i>.","authors":"Yujin Suzuki, Miki Kawada-Matsuo, Vy Ton That Thuan, Mi Nguyen-Tra Le, Takemasa Sakaguchi, Hitoshi Komatsuzawa","doi":"10.1128/aac.01936-24","DOIUrl":"https://doi.org/10.1128/aac.01936-24","url":null,"abstract":"<p><p>D-alanine is an important amino acid for peptidoglycan biosynthesis in <i>Staphylococcus aureus</i>. In addition, D-alanine is used for the modification of teichoic acids to weaken the net surface negative charge, leading to decreased susceptibility to cationic antimicrobial agents. D-alanine synthesis is dependent on only two enzymes. One is alanine racemase, encoded by the <i>alr1</i> gene, which reversibly converts L-alanine and D-alanine. The other is D-amino acid transaminase, encoded by the <i>dat</i> gene, which synthesizes D-amino acids from α-keto acids and other D-amino acids. In addition, the uptake of L- and D-alanine is dependent on the alanine transporter CycA. To reveal the relationship between D-alanine supply and antimicrobial susceptibility, we evaluated antimicrobial susceptibility in <i>alr1, dat,</i> and <i>cycA</i> inactivation mutants. These mutants, especially the Δ<i>alr1</i> and Δ<i>cycA</i> mutants, presented increased susceptibility to β-lactams, D-cycloserine, bacitracin, lysostaphin, and cationic antimicrobial agents such as aminoglycosides, nisin A, and daptomycin. The net negative charge of the cell surface increased in the Δ<i>alr1</i> and Δ<i>cycA</i> mutants. The changes in susceptibility to antimicrobial agents and cell surface charge were restored in their gene-complemented mutants. Furthermore, in an alanine-depleted medium, the MIC for oxacillin decreased significantly, and the MIC for gentamicin also decreased slightly. Clinical MRSA strains also showed significantly increased susceptibility to oxacillin in the alanine-depleted medium. These results indicate that D-alanine deficiency leads to impaired peptidoglycan and increased net surface negative charge, resulting in increased antimicrobial susceptibility.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0193624"},"PeriodicalIF":4.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population pharmacokinetic analyses for telavancin using data from healthy subjects and patients with infections.","authors":"Scott A Van Wart, M Courtney Safir, Sujata M Bhavnani, Thomas P Lodise, Christopher M Rubino","doi":"10.1128/aac.01382-24","DOIUrl":"https://doi.org/10.1128/aac.01382-24","url":null,"abstract":"<p><p>Telavancin is an intravenously administered lipoglycopeptide antibiotic active against clinically relevant gram-positive pathogens. In these analyses, a population pharmacokinetic (PK) model was constructed to describe the time course of telavancin in plasma and epithelial lining fluid (ELF) using data from healthy subjects and patients with complicated skin and skin-structure infections, hospital-acquired and ventilator-associated bacterial pneumonia, or uncomplicated bacteremia across Phases 1-4 of clinical development. Data from 1,205 individuals pooled from 21 studies contributed a total of 9,088 telavancin plasma concentrations. The final model for telavancin was a two-compartment model with zero-order intravenous input and linear elimination. Dialysis clearance was included as part of the base structural PK model; the relationship between telavancin clearance and creatinine clearance was included <i>a priori</i>. Body weight, age, and infection type were identified as statistically significant predictors of the interindividual variability (IIV) in total clearance. Body weight, age, and infection type were also identified as statistically significant predictors of IIV for the central and peripheral volumes of distribution. Only body weight was found to be a significant predictor of the IIV in distributional clearance. The model for ELF did not reveal any appreciable biases and determined the average free-drug ELF penetration ratio to be 73.0%. In summary, the population PK model characterized the time course of telavancin in both plasma and ELF robustly, captured the impact of clinically meaningful patient covariate effects, including removal of drug due to hemodialysis, and provided reliable individual <i>post hoc</i> estimates of exposure in subjects enrolled in the clinical studies.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0138224"},"PeriodicalIF":4.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two novel trimethoprim resistance genes, <i>dfra50</i> and <i>dfra51</i>, identified in phage-plasmids.","authors":"Kai Wang, Jikai Xu, Xiaowei Lu, Pan Yin, Li Chen, Ziwei Zhao, Alejandra Bravo, Mario Soberón, Jinshui Zheng, Ming Sun, Donghai Peng","doi":"10.1128/aac.01695-24","DOIUrl":"https://doi.org/10.1128/aac.01695-24","url":null,"abstract":"<p><p>Phage-plasmids carry a significant burden of clinically relevant antibiotic resistance genes (ARGs). Intriguingly, the majority of these ARGs are found within plasmids with phage features, with a single exception residing in a phage genome with plasmid features. Therefore, we speculate that phage genomes with plasmid features, whose sequences are highly homologous to bacterial plasmids, may carry novel ARGs. We subsequently identified 46 such phage genomes by employing Hidden Markov models (HMMs) based on plasmid-specific protein profiles andbasic local alignment search tool (BLASTn) searches against the National Center for Biotechnology Information (NCBI) RefSeq Plasmid Database. Among them, six phages harbored seven ARGs identified through a lenient-threshold search strategy, of which only two had been previously reported. The remaining five ARGs were categorized as novel ARGs since their encoded proteins differed from known ARGs. Notably, half of the phages carried trimethoprim-resistant <i>dfrA</i>-like genes. Functional studies characterized these genes and demonstrated that the expression of two of these <i>dfrA</i> genes (<i>dfrA50</i> and <i>dfrA51</i>) can confer resistance to trimethoprim in <i>Escherichia coli</i>. Through genome analysis, we found that these phages with plasmid features likely contributed to the natural dissemination of these <i>dfrA</i> genes, as evidenced by their widespread presence in plasmids across various pathogenic bacteria. These findings underscore the importance of identifying and monitoring ARGs encoded by phage genomes with plasmid features that also function as plasmids in bacteria, aiming to proactively address the antibiotic resistance challenges posed by these phage-mediated dissemination events.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0169524"},"PeriodicalIF":4.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure and mechanism of taniborbactam inhibition of the cefepime-hydrolyzing, partial R2-loop deletion <i>Pseudomonas</i>-derived cephalosporinase variant PDC-88.","authors":"Andrew R Mack, Vijay Kumar, Christopher R Bethel, Magdalena A Taracila, Brittany A Miller, Tsuyoshi Uehara, David A Six, Krisztina M Papp-Wallace, Focco van den Akker, Robert A Bonomo","doi":"10.1128/aac.00078-25","DOIUrl":"https://doi.org/10.1128/aac.00078-25","url":null,"abstract":"<p><p><i>Pseudomonas aeruginosa</i> is a major gram-negative pathogen responsible for a variety of infections and possessing an array of both intrinsic and acquired resistance mechanisms, including β-lactamases, like the chromosomal <i>Pseudomonas</i>-derived cephalosporinase (PDC). β-Lactams are the most widely prescribed class of antibiotics in the United States, and antipseudomonal cephalosporins (including cefepime) are important therapies (alone or combined with β-lactamase inhibitors) for <i>P. aeruginosa</i> infections. Taniborbactam is a novel, bicyclic boronate β-lactamase inhibitor with activity against all β-lactamase classes and is being developed in combination with cefepime. PDC-88 is an R2-loop deletion variant conferring resistance to cefepime and ceftazidime and elevating ceftolozane/tazobactam minimum inhibitory concentration (MIC). Herein, we elucidated PDC-88 resistance mechanisms and compared inhibition by taniborbactam and avibactam. In an isogenic background, PDC-88 increased cefepime MICs by 16-fold compared to PDC-3. <i>In vitro</i>, compared to PDC-3, PDC-88 had 8.3-fold higher catalytic efficiency for cefepime achieved by decreasing <i>K</i>_M 12.8-fold and decreasing <i>k</i>_cat 1.6-fold. This is supported by our crystallographic observation that the PDC-88 deletion enlarged the active site in the vicinity of the R2-loop, likely better accommodating cefepime. Taniborbactam and avibactam restored cefepime activity by inhibiting PDC-88. Compared to avibactam, taniborbactam had 4.1- and 9-fold lower <i>K</i>_{i app} values for PDC-3 and PDC-88, respectively, with higher <i>k</i>_on (<i>k</i>₂/<i>K</i>) and similar <i>k</i>_off for both enzymes. Structurally, taniborbactam positioned very similarly in the PDC-3 and PDC-88 active sites, interacting with many nearby residues. Based upon these data, cefepime-taniborbactam may represent an important alternative to ceftazidime-avibactam and ceftolozane-tazobactam for <i>P. aeruginosa</i> infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0007825"},"PeriodicalIF":4.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A propidium iodide-based <i>in vitro</i> screen of the \"Bug Box\" against <i>Babesia duncani</i> reveals potent inhibitors.","authors":"Emmett A Dews, José E Teixeira, Christopher D Huston, Marvin J Meyers, Peter R Hyson","doi":"10.1128/aac.00035-25","DOIUrl":"https://doi.org/10.1128/aac.00035-25","url":null,"abstract":"<p><p>The incidence and endemic range of human babesiosis are expanding. Standard therapy for human babesiosis consists of antimicrobials developed for other indications. While these treatments are adequate in immunocompetent hosts, infections in the immunocompromised can be severe, relapsing, and drug-resistant despite the use of multi-drug regimens. Existing drugs are ineffective in the immunocompromised because they cannot achieve and maintain adequate serum concentrations to inhibit <i>Babesia</i>. Discovery of improved agents against <i>Babesia</i> spp. is of growing importance, and efficient techniques for high-throughput compound screening can assist in this effort. We developed a high-throughput <i>in vitro</i> drug screening assay for <i>Babesia duncani</i> that is conducted in 384-well plates and makes use of the fluorescent DNA stain propidium iodide (PI) with relative fluorescence measured by a microplate reader. A Z' factor of 0.82 was calculated, which suggests an excellent ability to detect inhibitory compounds. A screen of the 41-compound library Structural Genomics Consortium Bug Box was conducted, yielding five hits: trimethoprim, atovaquone, SDDC M7, diphenyleneiodonium chloride, and panobinostat. Panobinostat, a histone deacetylase complex (HDAC) inhibitor, was selected for further evaluation given that its target had not been previously explored in <i>B. duncani</i>. Dose-response testing of structurally related compounds revealed multiple potential leads, including nanatinostat and quisinostat, both of which were potent at the nanomolar level and showed favorable selectivity index in cytotoxicity studies. High-throughput screening using PI and 384-well plates is an advance in drug discovery for babesiosis, and HDAC inhibitors show promise as lead compounds worthy of further investigation.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0003525"},"PeriodicalIF":4.1,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam.","authors":"Christophe Le Terrier, Salvador I Drusin, Patrice Nordmann, Johann Pitout, Gisele Peirano, Alejandro J Vila, Diego M Moreno, Laurent Poirel","doi":"10.1128/aac.00297-25","DOIUrl":"https://doi.org/10.1128/aac.00297-25","url":null,"abstract":"<p><p>Metallo-β-lactamases (MBLs) of IMP type are not inhibited by currently commercialized β-lactamase inhibitors, including taniborbactam (TAN), which inhibits only NDM- and VIM-type enzymes. However, the development of xeruborbactam (XER), which additionally inhibits IMP enzymes, may provide effective drug combinations such as meropenem-XER (MEM-XER) against most MBL producers. Thirty-two IMP-producing clinical gram-negative isolates were tested for MEM-XER. Susceptibility testing of β-lactams with TAN or XER at 4 or 8 µg/mL was performed. Noticeably, MEM-XER remained ineffective against all IMP-producing <i>Pseudomonas aeruginosa</i> isolates. By contrast, supplementation with XER significantly lowered MEM MICs for several IMP-producing <i>Enterobacterales</i> isolates, except for isolates and recombinant <i>E. coli</i> strains producing IMP-6, IMP-10, IMP-14, and IMP-26. Interestingly, IMP-59 producers showed susceptibility to both TAN- and XER-based combinations, although IMP enzymes are not supposed to be inhibited by TAN. Determinations of 50% inhibitory concentration (IC₅₀) values of XER showed values being >15-fold higher for IMP-6, IMP-10, IMP-14, and IMP-26 compared with IMP-1. Interestingly, the IC₅₀ value of TAN for IMP-59 was found in the same range as that for NDM-1 (7 µM). Finally, structural analyses and molecular modeling simulations indicated that the Ser262Gly mutation in IMP-6 may alter the electronic properties of the active site, whereas the Phe residue in IMP-10 may exert a steric effect counteracting XER binding. Resistance to XER in IMP-6, IMP-10, IMP-14, and IMP-26 variants, conferring resistance to MEM-XER, might be considered a serious concern since MEM-XER will be supposed to be a salvage therapy for MBL-, and especially IMP-producing <i>Enterobacterales</i> infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0029725"},"PeriodicalIF":4.1,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}