Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States
Katarzyna M Kedziora
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States; Bioinformatics and Analytics Research Collaborative, University of North Carolina at Chapel Hill, Chapel Hill, United States
Melina Arts
Institute for Pharmaceutical Microbiology, University of Bonn, Bonn, Germany
Jan-Martin Daniel
Institute for Pharmaceutical Microbiology, University of Bonn, Bonn, Germany
Stefania de Benedetti
Institute for Pharmaceutical Microbiology, University of Bonn, Bonn, Germany
Jenna E Beam
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States
Duyen T Bui
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States
Joshua B Parsons
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States; Division of Infectious Diseases, Duke University, Durham, United States
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States; Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States
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.
