TY - JOUR TI - Antibiotic-induced accumulation of lipid II synergizes with antimicrobial fatty acids to eradicate bacterial populations AU - Sidders, Ashelyn E AU - Kedziora, Katarzyna M AU - Arts, Melina AU - Daniel, Jan-Martin AU - de Benedetti, Stefania AU - Beam, Jenna E AU - Bui, Duyen T AU - Parsons, Joshua B AU - Schneider, Tanja AU - Rowe, Sarah E AU - Conlon, Brian P A2 - Helaine, Sophie A2 - Garrett, Wendy S A2 - Cassat, Jim VL - 12 PY - 2023 DA - 2023/03/06 SP - e80246 C1 - eLife 2023;12:e80246 DO - 10.7554/eLife.80246 UR - https://doi.org/10.7554/eLife.80246 AB - Antibiotic tolerance and antibiotic resistance are the two major obstacles to the efficient and reliable treatment of bacterial infections. Identifying antibiotic adjuvants that sensitize resistant and tolerant bacteria to antibiotic killing may lead to the development of superior treatments with improved outcomes. Vancomycin, a lipid II inhibitor, is a frontline antibiotic for treating methicillin-resistant Staphylococcus aureus and other Gram-positive bacterial infections. However, vancomycin use has led to the increasing prevalence of bacterial strains with reduced susceptibility to vancomycin. Here, we show that unsaturated fatty acids act as potent vancomycin adjuvants to rapidly kill a range of Gram-positive bacteria, including vancomycin-tolerant and resistant populations. The synergistic bactericidal activity relies on the accumulation of membrane-bound cell wall intermediates that generate large fluid patches in the membrane leading to protein delocalization, aberrant septal formation, and loss of membrane integrity. Our findings provide a natural therapeutic option that enhances vancomycin activity against difficult-to-treat pathogens, and the underlying mechanism may be further exploited to develop antimicrobials that target recalcitrant infection. KW - Staphylococcus aureus KW - antibiotic KW - adjuvant KW - lipid II KW - cell wall biosynthesis KW - unsaturated fatty acids JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -