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In this study, it is demonstrated that celastrol, a natural compound, can modify the bacterial cell wall and subsequently render bacteria more suceptible to \u03b2\u2010lactam antibiotics. It is shown that celastrol leads to incomplete cell wall crosslinking by modulating levels of c\u2010di\u2010AMP, a secondary messenger, in methicillin\u2010resistant <jats:italic>Staphylococcus aureus<\/jats:italic> (MRSA). This mechanism enables celastrol to act as a potentiator, effectively rendering MRSA susceptible to a range of penicillins and cephalosporins. Restoration of in vivo susceptibility of MRSA to methicillin is also demonstrated using a sepsis animal model by co\u2010administering methicillin along with celastrol at a much lower amount than that of methicillin. The results suggest a novel approach for developing potentiators for major classes of antibiotics by exploring molecules that re\u2010program metabolic pathways to reverse \u03b2\u2010lactam\u2010resistant strains to susceptible strains.<\/jats:p>","DOI":"10.1002\/advs.202400858","type":"journal-article","created":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T04:58:03Z","timestamp":1715749083000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Reducing Peptidoglycan Crosslinking by Chemical Modulator Reverts \u03b2\u2010lactam Resistance in Methicillin\u2010Resistant <i>Staphylococcus aureus<\/i>"],"prefix":"10.1002","volume":"11","author":[{"given":"Ji\u2010Hoon","family":"Kim","sequence":"first","affiliation":[{"name":"School of Pharmacy Sungkyunkwan University  Suwon 16419 Republic of 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