{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:25:11Z","timestamp":1760059511110,"version":"build-2065373602"},"reference-count":31,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01AI177997","I01BX004677-01"],"award-info":[{"award-number":["R01AI177997","I01BX004677-01"]}]},{"DOI":"10.13039\/100000738","name":"Department of Veterans Affairs VA Merit Review","doi-asserted-by":"publisher","award":["R01AI177997","I01BX004677-01"],"award-info":[{"award-number":["R01AI177997","I01BX004677-01"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: The increasing occurrence of carbapenem resistance A. baumannii (CRAB) has forced clinicians to seek out alternative options with activity against CRAB. CRAB with inactivated PBP7\/8 has been shown to result in an increased outer membrane permeability and could serve as a potential new adjuvant target. Methods: Two isogenic clinical isolates of A. baumannii HUMC1 were utilized (WT and HUMC1 \u0394PBP7\/8). Static concentration time-kill assays were performed against both isolates with escalating exposures to antibiotics. The resulting data were modeled using the Monolix software suite to capture parameters related to bacterial killing and PBP7\/8 synergism. The model results were used to prospectively simulate clinically relevant antibiotic dosing of three antibiotics under physiological conditions and were validated using a hollow-fiber infection model (HFIM). Results: Treatment with monotherapy or combination therapy resulted in concentration-dependent killing for both isolates. Bacterial killing was greater with HUMC1 \u0394PBP7\/8 for all tested antibiotic concentrations. The mean bacterial population reduction was 4.38 log10 CFU\/mL for HUMC1 and 5.38 log10 CFU\/mL for HUMC1\u0394PBP7\/8 knockout isolate. The final mechanism-based model demonstrated improved antibacterial activity with PBP7\/8 inhibition through a decline in KC50 values of 59.7% across the beta-lactams in the PBP7\/8 knockout. HFIM observations that were retrospectively compared to the simulated model-predicted bacterial concentration time course showed our final model was able to appropriately capture changes in bacterial population within a dynamic HFIM scenario. Conclusions: The quantification of KC50 decline and increase in effectiveness of previously sidelined antimicrobial therapies with PBP7\/8 inhibition suggests PBP7\/8 is a promising potential target for an antibacterial adjuvant. This lends further support to advance to next-stage studies for identifying compounds that specifically inhibit PBP7\/8 activity.<\/jats:p>","DOI":"10.3390\/ph18060918","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T09:57:48Z","timestamp":1750327068000},"page":"918","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacodynamic Evaluation of Adjuvant Targets: Low Molecular Weight PBP7\/8 Effects on \u03b2-Lactam Activity Against Carbapenem-Resistant Acinetobacter Baumannii"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9229-4131","authenticated-orcid":false,"given":"Brian M.","family":"Ho","sequence":"first","affiliation":[{"name":"Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingxiu","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob T.","family":"Sanborn","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas D.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Navaldeep","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nader N.","family":"Nasief","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrike","family":"Carlino-MacDonald","sequence":"additional","affiliation":[{"name":"Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14203, USA"},{"name":"Veterans Administration Western New York Healthcare System, Buffalo, NY 14215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian T.","family":"Tsuji","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2664-2795","authenticated-orcid":false,"given":"Yanan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5845-2235","authenticated-orcid":false,"given":"Liang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6404-246X","authenticated-orcid":false,"given":"Bartolome","family":"Moya","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n, Hospital Universitario Son Espases, Instituto de Investigaci\u00f3n Sanitaria Illes Balears (IdISBa), 07120 Palma, Balearic Islands, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Infecciosas (CIBERINFEC), 07120 Palma, Balearic Islands, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4566-7442","authenticated-orcid":false,"given":"Thomas A.","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14203, USA"},{"name":"Veterans Administration Western New York Healthcare System, Buffalo, NY 14215, USA"},{"name":"The Witebsky Center for Microbial Pathogenesis, University at Buffalo, The State University of New York, Buffalo, NY 14203, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0212-2787","authenticated-orcid":false,"given":"Nicholas M.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1086\/529198","article-title":"Acinetobacter baumannii: Epidemiology, antimicrobial resistance, and treatment options","volume":"46","author":"Maragakis","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Chen, W. (2020). Host Innate Immune Responses to Acinetobacter baumannii Infection. Front. Cell Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.00486"},{"key":"ref_3","unstructured":"CDC (2022). COVID-19: U.S. Impact on Antimicrobial Resistance, Special Report 2022."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1128\/CMR.00058-07","article-title":"Acinetobacter baumannii: Emergence of a successful pathogen","volume":"21","author":"Peleg","year":"2008","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_5","unstructured":"CDC (2019). Antibiotic Resistance Threats in the United States, 2019."},{"key":"ref_6","first-page":"e000306","article-title":"Emergence, molecular mechanisms and global spread of carbapenem-resistant Acinetobacter baumannii","volume":"5","author":"Hamidian","year":"2019","journal-title":"Microb. Genom."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2659","DOI":"10.1128\/AAC.47.8.2659-2662.2003","article-title":"Polymyxin B nephrotoxicity and efficacy against nosocomial infections caused by multiresistant gram-negative bacteria","volume":"47","author":"Ouderkirk","year":"2003","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.idc.2016.02.005","article-title":"Agents of Last Resort: Polymyxin Resistance","volume":"30","author":"Kaye","year":"2016","journal-title":"Infect. Dis. Clin. N. Am."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1093\/jac\/dkm305","article-title":"High rates of resistance to colistin and polymyxin B in subgroups of Acinetobacter baumannii isolates from Korea","volume":"60","author":"Ko","year":"2007","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S565","DOI":"10.1093\/cid\/ciz830","article-title":"Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections","volume":"69","author":"Doi","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Isler, B., Doi, Y., Bonomo, R.A., and Paterson, D.L. (2019). New Treatment Options against Carbapenem-Resistant Acinetobacter baumannii Infections. Antimicrob. Agents Chemother., 63.","DOI":"10.1128\/AAC.01110-18"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1111\/j.1574-6976.2008.00105.x","article-title":"The penicillin-binding proteins: Structure and role in peptidoglycan biosynthesis","volume":"32","author":"Sauvage","year":"2008","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3981","DOI":"10.1128\/JB.181.13.3981-3993.1999","article-title":"Escherichia coli mutants lacking all possible combinations of eight penicillin binding proteins: Viability, characteristics, and implications for peptidoglycan synthesis","volume":"181","author":"Denome","year":"1999","journal-title":"J. Bacteriol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1111\/j.1574-6976.2007.00095.x","article-title":"Penicillin-binding proteins and beta-lactam resistance","volume":"32","author":"Zapun","year":"2008","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1086\/596317","article-title":"Penicillin-binding protein 7\/8 contributes to the survival of Acinetobacter baumannii in vitro and in vivo","volume":"199","author":"Russo","year":"2009","journal-title":"J. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e0103322","DOI":"10.1128\/aac.01033-22","article-title":"Penicillin Binding Protein 7\/8 Is a Potential Drug Target in Carbapenem-Resistant Acinetobacter baumannii","volume":"67","author":"Russo","year":"2023","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"742","DOI":"10.7164\/antibiotics.45.742","article-title":"Polymyxin B octapeptide and polymyxin B heptapeptide are potent outer membrane permeability-increasing agents","volume":"45","author":"Kimura","year":"1992","journal-title":"J. Antibiot."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1177\/2042098614554919","article-title":"Antimicrobial resistance: Risk associated with antibiotic overuse and initiatives to reduce the problem","volume":"5","author":"Llor","year":"2014","journal-title":"Ther. Adv. Drug Saf."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e0139923","DOI":"10.1128\/aac.01399-23","article-title":"Comprehensive stability analysis of 13 beta-lactams and beta-lactamase inhibitors in in vitro media, and novel supplement dosing strategy to mitigate thermal drug degradation","volume":"68","author":"Zhou","year":"2024","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1002\/jcph.810","article-title":"Evaluation of Aztreonam Dosing Regimens in Patients With Normal and Impaired Renal Function: A Population Pharmacokinetic Modeling and Monte Carlo Simulation Analysis","volume":"57","author":"Xu","year":"2017","journal-title":"J. Clin. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2622","DOI":"10.1093\/jac\/dkaa197","article-title":"Determining the optimal dosing of a novel combination regimen of ceftazidime\/avibactam with aztreonam against NDM-1-producing Enterobacteriaceae using a hollow-fibre infection model","volume":"75","author":"Lodise","year":"2020","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1111\/bcp.12901","article-title":"Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid","volume":"81","author":"Rizk","year":"2016","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1086\/514622","article-title":"The pharmacodynamics of beta-lactams","volume":"27","author":"Turnidge","year":"1998","journal-title":"Clin. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1016\/j.cmi.2020.02.004","article-title":"Using machine learning to optimize antibiotic combinations: Dosing strategies for meropenem and polymyxin B against carbapenem-resistant Acinetobacter baumannii","volume":"26","author":"Smith","year":"2020","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2825","DOI":"10.1093\/jac\/dkz226","article-title":"Inoculum effect of beta-lactam antibiotics","volume":"74","author":"Lenhard","year":"2019","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Luna, B.M., Ulhaq, A., Yan, J., Pantapalangkoor, P., Nielsen, T.B., Davies, B.W., Actis, L.A., and Spellberg, B. (2017). Selectable Markers for Use in Genetic Manipulation of Extensively Drug-Resistant (XDR) Acinetobacter baumannii HUMC1. mSphere, 2.","DOI":"10.1128\/mSphere.00140-17"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1592\/phco.26.9.1320","article-title":"Application of antimicrobial pharmacodynamic concepts into clinical practice: Focus on beta-lactam antibiotics: Insights from the Society of Infectious Diseases Pharmacists","volume":"26","author":"Lodise","year":"2006","journal-title":"Pharmacotherapy"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3366","DOI":"10.1128\/AAC.00080-14","article-title":"Activities of ceftazidime and avibactam against beta-lactamase-producing Enterobacteriaceae in a hollow-fiber pharmacodynamic model","volume":"58","author":"Coleman","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1128\/AAC.00489-08","article-title":"Development and qualification of a pharmacodynamic model for the pronounced inoculum effect of ceftazidime against Pseudomonas aeruginosa","volume":"53","author":"Bulitta","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1086\/424849","article-title":"Selection of a moxifloxacin dose that suppresses drug resistance in Mycobacterium tuberculosis, by use of an in vitro pharmacodynamic infection model and mathematical modeling","volume":"190","author":"Gumbo","year":"2004","journal-title":"J. Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1093\/cid\/cit334","article-title":"Population pharmacokinetics of intravenous polymyxin B in critically ill patients: Implications for selection of dosage regimens","volume":"57","author":"Sandri","year":"2013","journal-title":"Clin. Infect. Dis."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/6\/918\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:54:35Z","timestamp":1760032475000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/6\/918"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,18]]},"references-count":31,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["ph18060918"],"URL":"https:\/\/doi.org\/10.3390\/ph18060918","relation":{},"ISSN":["1424-8247"],"issn-type":[{"type":"electronic","value":"1424-8247"}],"subject":[],"published":{"date-parts":[[2025,6,18]]}}}