Antimicrobial Agents and Chemotherapy最新文献

{"title":"Zidovudine in synergistic combination with nitrofurantoin or omadacycline: <i>in vitro</i> and in murine urinary tract or lung infection evaluation against multidrug-resistant <i>Klebsiella pneumoniae</i>.","authors":"Ping Tian, Qing-Qing Li, Ming-Juan Guo, Yun-Zhu Zhu, Rong-Qing Zhu, Ya-Qin Guo, Yi Yang, Yan-Yan Liu, Liang Yu, Ya-Sheng Li, Jia-Bin Li","doi":"10.1128/aac.00344-24","DOIUrl":"https://doi.org/10.1128/aac.00344-24","url":null,"abstract":"<p><p>Limited treatment options and multidrug-resistant (MDR) <i>Klebsiella pneumoniae</i> present a significant therapeutic challenge, underscoring the need for novel approaches. Drug repurposing is a promising tool for augmenting the activity of many antibiotics. This study aimed to identify novel synergistic drug combinations against <i>K. pneumoniae</i> based on drug repurposing. We used the clinically isolated GN 172867 MDR strain of <i>K. pneumoniae</i> to determine the reversal resistance activity of zidovudine (AZT). The combined effects of AZT and various antibiotics, including nitrofurantoin (NIT) and omadacycline (OMC), were examined using the checkerboard method, growth curves, and crystal violet assays to assess biofilms. An <i>in vitro</i> combination activity testing was carried out in 12 isolates of <i>K. pneumoniae. In vivo</i> murine urinary tract and lung infection models were used to evaluate the therapeutic effects of AZT + NIT and AZT + OMC, respectively. The fractional inhibitory concentration index and growth curve demonstrated that AZT synergized with NIT or OMC against <i>K. pneumoniae</i> strains. In addition, AZT + NIT inhibited biofilm formation and cleared mature biofilms. <i>In vivo</i>, compared with untreated GN 172867-infected mice, AZT + NIT and AZT + OMC treatment decreased colony counts in multiple tissues (<i>P</i> < 0.05) and pathological scores in the bladder and kidneys (<i>P</i> < 0.05) and increased the survival rate by 60% (<i>P</i> < 0.05). This study evaluated the combination of AZT and antibiotics to treat drug-resistant <i>K. pneumoniae</i> infections and found novel drug combinations for the treatment of acute urinary tract infections. These findings suggest that AZT may exert significant anti-resistance activity.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078880","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":"Identification of novel and potent inhibitors of SARS-CoV-2 main protease from DNA-encoded chemical libraries.","authors":"Dario Akaberi, Monireh Pourghasemi Lati, Janina Krambrich, Julia Berger, Grace Neilsen, Emilia Strandback, S Pauliina Turunen, Johan Wannberg, Hjalmar Gullberg, Martin Moche, Praveen Kumar Chinthakindi, Tomas Nyman, Stefan G Sarafianos, Anja Sandström, Josef D Järhult, Kristian Sandberg, Åke Lundkvist, Oscar Verho, Johan Lennerstrand","doi":"10.1128/aac.00909-24","DOIUrl":"https://doi.org/10.1128/aac.00909-24","url":null,"abstract":"<p><p><i>In vitro</i> screening of large compound libraries with automated high-throughput screening is expensive and time-consuming and requires dedicated infrastructures. Conversely, the selection of DNA-encoded chemical libraries (DECLs) can be rapidly performed with routine equipment available in most laboratories. In this study, we identified novel inhibitors of SARS-CoV-2 main protease (M^pro) through the affinity-based selection of the DELopen library (open access for academics), containing 4.2 billion compounds. The identified inhibitors were peptide-like compounds containing an N-terminal electrophilic group able to form a covalent bond with the nucleophilic Cys145 of M^pro, as confirmed by x-ray crystallography. This DECL selection campaign enabled the discovery of the unoptimized compound SLL11 (IC₅₀ = 30 nM), proving that the rapid exploration of large chemical spaces enabled by DECL technology allows for the direct identification of potent inhibitors avoiding several rounds of iterative medicinal chemistry. As demonstrated further by x-ray crystallography, SLL11 was found to adopt a highly unique U-shaped binding conformation, which allows the N-terminal electrophilic group to loop back to the S1' subsite while the C-terminal amino acid sits in the S1 subsite. MP1, a close analog of SLL11, showed antiviral activity against SARS-CoV-2 in the low micromolar range when tested in Caco-2 and Calu-3 (EC₅₀ = 2.3 µM) cell lines. As peptide-like compounds can suffer from low cell permeability and metabolic stability, the cyclization of the compounds will be explored in the future to improve their antiviral activity.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078849","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":"IncC plasmid genome rearrangements influence the vertical and horizontal transmission tradeoff in <i>Escherichia coli</i>.","authors":"Margaux Allain, Thibaut Morel-Journel, Bénédicte Condamine, Benoist Gibeaux, Benoit Gachet, Rémi Gschwind, Erick Denamur, Luce Landraud","doi":"10.1128/aac.00554-24","DOIUrl":"https://doi.org/10.1128/aac.00554-24","url":null,"abstract":"<p><p>It has been shown that an evolutionary tradeoff between vertical (host growth rate) and horizontal (plasmid conjugation) transmissions contributes to global plasmid fitness. As conjugative IncC plasmids are important for the spread of multidrug resistance (MDR), in a broad range of bacterial hosts, we investigated vertical and horizontal transmissions of two multidrug-resistant IncC plasmids according to their backbones and MDR-region rearrangements, upon plasmid entry into a new host. We observed plasmid genome deletions after conjugation in three diverse natural <i>Escherichia coli</i> clinical strains, varying from null to high number depending on the plasmid, all occurring in the MDR region. The plasmid burden on bacterial fitness depended more on the strain background than on the structure of the MDR region, with deletions appearing to have no impact. Besides, we observed an increase in plasmid transfer rate, from ancestral host to new clinical recipient strains, when the IncC plasmid was rearranged. Finally, using a second set of conjugation experiments, we investigated the evolutionary tradeoff of the IncC plasmid during the critical period of plasmid establishment in <i>E. coli</i> K-12, by correlating the transfer rates of deleted or non-deleted IncC plasmids and their costs on the recipient strain. Plasmid deletions strongly improved conjugation efficiency with no negative growth effect. Our findings indicate that the flexibility of the MDR-region of the IncC plasmids can promote their dissemination, and provide diverse opportunities to capture new resistance genes. In a broader view, they suggest that the vertical-horizontal transmission tradeoff can be manipulated by the plasmid to improve its fitness.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078850","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":"Adjuvants restore colistin sensitivity in mouse models of highly colistin-resistant isolates, limiting bacterial proliferation and dissemination.","authors":"Beverly H Koller, Leigh A Jania, Haoting Li, William T Barker, Roberta J Melander, Christian Melander","doi":"10.1128/aac.00671-24","DOIUrl":"https://doi.org/10.1128/aac.00671-24","url":null,"abstract":"<p><p>Antimicrobial resistance (AMR) has led to a marked reduction in the effectiveness of many antibiotics, representing a substantial and escalating concern for global health. Particularly alarming is resistance in Gram-negative bacteria due to the scarcity of therapeutic options for treating infections caused by these pathogens. This challenge is further compounded by the rising incidence of resistance to colistin, an antibiotic traditionally considered a last resort for the treatment of multi-drug resistant (MDR) Gram-negative bacterial infections. In this study, we demonstrate that adjuvants restore colistin sensitivity <i>in vivo</i>. We previously reported that the salicylanilide kinase inhibitor IMD-0354, which was originally developed to inhibit the human kinase IKKβ in the NFκB pathway, is a potent colistin adjuvant. Subsequent analog synthesis using an amide isostere approach led to the creation of a series of novel benzimidazole compounds with enhanced colistin adjuvant activity. Herein, we demonstrate that both IMD-0354 and a lead benzimidazole effectively restore colistin susceptibility in mouse models of highly colistin-resistant <i>Klebsiella pneumoniae</i> and <i>Acinetobacter baumannii</i>-induced peritonitis. These novel adjuvants show low toxicity <i>in vivo</i>, significantly reduce bacterial load, and prevent dissemination that could otherwise result in systemic infection.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078845","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":"Dose-fractionation studies of a <i>Plasmodium</i> phosphatidylinositol 4-kinase inhibitor in a humanized mouse model of malaria.","authors":"Liezl Gibhard, Mathew Njoroge, Mwila Mulubwa, Nina Lawrence, Dennis Smith, James Duffy, Claire Le Manach, Christel Brunschwig, Dale Taylor, Renier van der Westhuyzen, Leslie J Street, Gregory S Basarab, Kelly Chibale","doi":"10.1128/aac.00842-24","DOIUrl":"https://doi.org/10.1128/aac.00842-24","url":null,"abstract":"<p><p>UCT594 is a 2-aminopyrazine carboxylic acid <i>Plasmodium</i> phosphatidylinositol 4-kinase inhibitor with potent asexual blood-stage activity, the potential for interrupting transmission, as well as liver-stage activities. Herein, we investigated pharmacokinetic/pharmacodynamic (PK/PD) relationships relative to blood-stage activity toward predicting the human dose. Dose-fractionation studies were conducted in the <i>Plasmodium falciparum</i> NSG mouse model to determine the PK/PD indices of UCT594, using the <i>in vivo</i> minimum parasiticidal concentration as a threshold. UCT594 demonstrated concentration-dependent killing in the <i>P. falciparum</i>-infected NSG mouse model. Using this data and the preclinical pharmacokinetic data led to a low predicted human dose of <50 mg. This makes UCT594 an attractive potential antimalarial drug.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078848","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":"<i>Acinetobacter baumannii</i> transformants expressing oxacillinases and metallo-β-lactamases that confer resistance to meropenem: new tools for anti-<i>Acinetobacter</i> drug development and AMR preparedness.","authors":"Vineet Dubey, Nicola Farrington, Nicholas Harper, Adam Johnson, Iona Horner, Adam Stevenson, Annie Parkes, Lewis Hoare, Shampa Das, William Hope","doi":"10.1128/aac.00222-24","DOIUrl":"https://doi.org/10.1128/aac.00222-24","url":null,"abstract":"<p><p>Antimicrobial resistance (AMR) in <i>Acinetobacter baumannii</i> is an unmet medical need. Multiple drug-resistant/extremely drug-resistant strains of <i>A. baumannii</i> do not display growth well in <i>in vivo</i> models, and consequently, their response to antibacterial therapy is inconsistent. We addressed this issue by engineering carbapenem resistance motifs into the highly virulent genetic background of <i>A. baumannii</i> AB5075. This strain has a chromosomally encoded <i>oxa-23</i> that was deleted (<i>Δoxa-23</i>), then plasmids expressing <i>oxa-23</i>, <i>oxa-24/40</i>, <i>oxa-58</i>, <i>imp-1</i>, <i>vim-2</i>, and <i>ndm-1</i> were introduced to create the mutant strains. Each transformant was used as a challenge strain in a neutropenic murine thigh infection model and assessed for the extent of growth and response to meropenem 200 mg/kg subcutaneously every 6 h (q6h). Pharmacodynamic analyses were performed by transforming drug exposure from dose (mg/kg) to the fraction of the dosing interval; free meropenem concentrations were >minimum inhibitory concentration (MIC) (<i>f</i>T > MIC). AB5075 and the AB5075<i>Δoxa-23</i> mutant had a MICs of 32 and 4 mg/L, respectively. The transformants harboring oxacillinases <i>oxa-24/40</i> and <i>oxa-58</i> had an MIC of 64 mg/L. The metallo-β-lactamases <i>imp-1</i>, <i>vim-2</i>, and <i>ndm-1</i> had MICs of 128, 64, and 64 mg/L, respectively. All vehicle-treated transformants displayed <i>in vivo</i> growth in the range of 0.75-1.4 log. The response to meropenem was consistent with the varying <i>f</i>T > MIC of the transformants and was readily described by an inhibitory sigmoid <i>E</i>_max relationship. Stasis was achieved with a <i>f</i>T > MIC of 0.36. These <i>A. baumannii</i> transformants are invaluable new tools for the assessment of anti-<i>Acinetobacter</i> compounds and provide a new pathway for AMR preparedness.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071808","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":"Deoxyshikonin: a promising lead drug grass against drug resistance or sensitivity to <i>Helicobacter pylori</i> in an acidic environment.","authors":"Jia-Yin Xu, Hui-Hua Dong, Li-Juan Liao, Shi-Xian Yang, Lu-Yao Wang, Hao Chen, Peipei Luo, Liang Huang, Ai-Xing Guan, Yan-Qiang Huang","doi":"10.1128/aac.00959-24","DOIUrl":"https://doi.org/10.1128/aac.00959-24","url":null,"abstract":"<p><p><i>Helicobacter pylori</i> (<i>H. pylori</i>) is closely associated with the diseases such as gastric sinusitis, peptic ulcers, and gastric adenocarcinoma. Its drug resistance is very severe, and new antibiotics are urgently needed. Nine comfrey compounds were screened by antimicrobial susceptibility testing, among which deoxyshikonin had the best inhibitory effect, with a minimum inhibitory concentration (MIC) of 0.5-1 µg/mL. In addition, deoxyshikonin also has a good antibacterial effect in an acidic environment, it is highly safe, and <i>H. pylori</i> does not readily develop drug resistance. Through <i>in vivo</i> experiments, it was proven that deoxyshikonin (7 mg/kg) had a beneficial therapeutic effect on acute gastritis in mice infected with the multidrug-resistant <i>H. pylori</i> BS001 strain. After treatment with desoxyshikonin, colonization of <i>H. pylori</i> in the gastric mucosa of mice was significantly reduced, gastric mucosal damage was repaired, inflammatory factors were reduced, and the treatment effect was better than that of standard triple therapy. Therefore, deoxyshikonin is a promising lead drug to solve the difficulty of drug resistance in <i>H. pylori</i>, and its antibacterial mechanism may be to destroy the biofilm and cause an oxidation reaction.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016180","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":"Use of frozen native feces for fecal microbiota transplantation in recurrent <i>Clostridioides difficile</i> infection: a simple way to improve the efficiency of donor feces preparation.","authors":"Rachel Sintes, Paul McLellan, Gabriele Navelli, Cécilia Landman, Sandrine Delage, Sandrine Truong, Nicolas Benech, Nathalie Kapel, Alicia Moreino Sabater, Aurélie Schnuriger, Catherine Eckert, Alexandre Bleibtreu, Anne-Christine Joly, Harry Sokol","doi":"10.1128/aac.00734-24","DOIUrl":"https://doi.org/10.1128/aac.00734-24","url":null,"abstract":"<p><p>Preparing fecal microbiota transplants immediately after donation is resource-intensive, and a proportion are destroyed following abnormal screening results. We retrospectively compared two processes, frozen fecal preparation (FFP) and fresh native frozen preparation (FNFP), for clinical efficacy in the treatment of recurrent <i>Clostridioides difficile</i> infection (rCDI). FFP and FNFP were similarly effective with clinical success rates of 76.7% and 86.7% (<i>P</i> = 0.32), respectively. FNFP is an efficient procedure that saves resources while maintaining clinical efficacy in rCDI.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016181","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":"Structural basis of paramyxo- and pneumovirus polymerase inhibition by non-nucleoside small-molecule antivirals.","authors":"Josef D Wolf, Michael R Sirrine, Robert M Cox, Richard K Plemper","doi":"10.1128/aac.00800-24","DOIUrl":"https://doi.org/10.1128/aac.00800-24","url":null,"abstract":"<p><p>Small-molecule antivirals can be used as chemical probes to stabilize transitory conformational stages of viral target proteins, facilitating structural analyses. Here, we evaluate allosteric pneumo- and paramyxovirus polymerase inhibitors that have the potential to serve as chemical probes and aid the structural characterization of short-lived intermediate conformations of the polymerase complex. Of multiple inhibitor classes evaluated, we discuss in-depth distinct scaffolds that were selected based on well-understood structure-activity relationships, insight into resistance profiles, biochemical characterization of the mechanism of action, and photoaffinity-based target mapping. Each class is thought to block structural rearrangements of polymerase domains albeit target sites and docking poses are distinct. This review highlights validated druggable targets in the paramyxo- and pneumovirus polymerase proteins and discusses discrete structural stages of the polymerase complexes required for bioactivity.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003479","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 molecular analysis of meropenem-vaborbactam non-susceptible KPC-producing <i>Klebsiella pneumoniae</i>.","authors":"Mohamad Yasmin, Steven H Marshall, Liang Chen, Daniel D Rhoads, Michael R Jacobs, Laura J Rojas, Federico Perez, Andrea M Hujer, Kristine M Hujer, David van Duin, Vance Fowler, Henry F Chambers, Barry N Kreiswirth, Robert A Bonomo","doi":"10.1128/aac.00208-24","DOIUrl":"https://doi.org/10.1128/aac.00208-24","url":null,"abstract":"<p><p>We characterized the molecular determinants of meropenem-vaborbactam (MV) non-susceptibility among non-metallo-β-lactamase-producing KPC-<i>Klebsiella pneumoniae</i> (KPC-<i>KP</i>). Whole-genome sequencing was performed to identify mutations associated with MV non-susceptibility. Isolates with elevated MV MICs were found to have mutations encoding truncated or altered OmpK36 porins and increased <i>bla</i>_KPC copy numbers. KPC-<i>KP</i> isolates with decreased susceptibility to MV were detected among a collection of isolates predating the availability of MV.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003478","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}