![]() Disruption of any component sensitizes the outer membrane and reduces its ability to exclude compounds. LPS consists of three major components: the surface O-antigen polysaccharide, the saccharide core, and the membrane bound lipid A. This barrier is maintained by lipopolysaccharides (LPS) in the external leaflet of the outer membrane and by efflux pumps that span both membranes and the periplasm. The presence of an outer membrane barrier prevents many antibiotics from accessing the cell. Gram negative bacterial pathogens are equipped with numerous defenses that make them inherently difficult to treat. The funders did not play any role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the manuscript.įunding: The work was supported by National Institutes of Health grants AI126453 (CSD), AI121365 (CSD), GM126960 (JS), and AI145069 (EWY). Received: JAccepted: NovemPublished: December 8, 2020Ĭopyright: © 2020 Dombach et al. PLoS Pathog 16(12):Įditor: Leigh Knodler, Washington State University, UNITED STATES (2020) A small molecule that mitigates bacterial infection disrupts Gram-negative cell membranes and is inhibited by cholesterol and neutral lipids. This is the first compound, to our knowledge, that preferentially targets the cell membranes of Gram-negative bacteria and reduces bacterial infection of animals.Ĭitation: Dombach JL, Quintana JLJ, Nagy TA, Wan C, Crooks AL, Yu H, et al. JD1 also decreases bacterial colonization of infected mice. ![]() We present data showing that the compound JD1 disrupts bacterial cell membranes, a structure not targeted by current antibiotics for Gram-negative bacteria. We focused our efforts on Gram-negative bacteria because this class of pathogens is particularly difficult to treat with antibiotics. To find such a compound, we looked for chemicals that reduce the number of infectious bacteria within mammalian cells. To decrease the likelihood that bacteria will rapidly develop resistance to new antibacterials, researchers are seeking novel compounds that work differently than existing antibiotics. It has even been predicted that in the next thirty years there will be more deaths from antibiotic resistant infections than from cancer. Thus, it may be possible to develop therapeutics that exploit host innate immunity to gain access to Gram-negative bacteria and then preferentially damage the bacterial cell membrane over host membranes.īacteria are increasingly becoming resistant to the antibiotics that are currently available. These observations indicate that during infection, JD1 gains access to and disrupts the cytoplasmic membrane of Gram-negative bacteria, and that neutral lipids and cholesterol protect mammalian membranes from JD1-mediated damage. In mice, intraperitoneal administration of JD1 reduced tissue colonization by S. Cholesterol, a component of mammalian cell membranes, was protective in the presence of neutral lipids. coli inner membranes versus mammalian cell membranes. Moreover, JD1 preferentially damaged liposomes with compositions similar to E. We quantified macrophage cell membrane integrity and mitochondrial membrane potential and found that disruption of eukaryotic cell membranes required approximately 30-fold more JD1 than was needed to kill bacteria in macrophages. Using a combination of cellular indicators and super resolution microscopy, we found that JD1 damaged bacterial cytoplasmic membranes by increasing fluidity, disrupting barrier function, and causing the formation of membrane distortions. JD1 is not antibacterial in standard microbiological media, but rapidly inhibits growth and curtails bacterial survival under broth conditions that compromise the outer membrane or reduce efflux pump activity. Typhimurium) residing within macrophages. Using chemical genetics, we recently identified a small molecule, JD1, that kills Salmonella enterica serovar Typhimurium ( S. However, mammals have evolved a substantial immune arsenal that weakens pathogen defenses, suggesting the feasibility of developing therapies that work in concert with innate immunity to kill Gram-negative bacteria. Infections caused by Gram-negative bacteria are difficult to fight because these pathogens exclude or expel many clinical antibiotics and host defense molecules.
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