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It is imperative that we create new mechanistic insights based on latest technologies, and use translational strategies to optimize patient therapy. Although drug development has relied on minimal inhibitory concentration testing and established <jats:italic>in vitro<\/jats:italic> and mouse infection models, the limited understanding of outer membrane permeability in Gram\u2010negative bacteria presents major challenges. Our team has developed a platform using the latest technologies to characterize target site penetration and receptor binding in intact bacteria that inform translational modeling and guide new discovery. Enhanced assays can quantify the outer membrane permeability of \u03b2\u2010lactam antibiotics and \u03b2\u2010lactamase inhibitors using multiplex liquid chromatography tandem mass spectrometry. While \u03b2\u2010lactam antibiotics are known to bind to multiple different penicillin\u2010binding proteins (PBPs), their binding profiles are almost always studied in lysed bacteria. Novel assays for PBP binding in the periplasm of intact bacteria were developed and proteins identified via proteomics. To characterize bacterial morphology changes in response to PBP binding, high\u2010throughput flow cytometry and time\u2010lapse confocal microscopy with fluorescent probes provide unprecedented mechanistic insights. Moreover, novel assays to quantify cytosolic receptor binding and intracellular drug concentrations inform target site occupancy. These mechanistic data are integrated by quantitative and systems pharmacology modeling to maximize bacterial killing and minimize resistance in <jats:italic>in vitro<\/jats:italic> and mouse infection models. This translational approach holds promise to identify antibiotic combination dosing strategies for patients with serious infections.<\/jats:p>","DOI":"10.1002\/cpt.2205","type":"journal-article","created":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T04:32:09Z","timestamp":1613277129000},"page":"1000-1020","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Combating Multidrug\u2010Resistant Bacteria by Integrating a Novel Target Site Penetration and Receptor Binding Assay Platform Into Translational Modeling"],"prefix":"10.1111","volume":"109","author":[{"given":"Yinzhi","family":"Lang","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research College of Pharmacy University of Florida Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nirav R.","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research College of Pharmacy University of Florida Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xun","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research College of Pharmacy University of Florida Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie M.","family":"Reeve","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology and Therapeutics St. Jude Children\u2019s Research Hospital Memphis Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jieqiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research College of Pharmacy University of Florida Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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) Palma de Mallorca Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alaa R. 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