title: A new antibiotic with potent activity targets MscL.
abstract: The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections.
authors: Department of Physiology, UT Southwestern Med Ctr, Dallas, TX, USA.
authors: Irene
authors: 000000018936430X
authors: I
authors: Iscla
authors: Department of Physiology, UT Southwestern Med Ctr, Dallas, TX, USA.
authors: Robin
authors: R
authors: Wray
authors: Department of Physiology, UT Southwestern Med Ctr, Dallas, TX, USA.
authors: Paul
authors: P
authors: Blount
authors: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
authors: Jonah
authors: J
authors: Larkins-Ford
authors: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
authors: Annie L
authors: AL
authors: Conery
authors: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
authors: Frederick M
authors: FM
authors: Ausubel
authors: Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia.
authors: Soumya
authors: S
authors: Ramu
authors: Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia.
authors: Angela
authors: A
authors: Kavanagh
authors: Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia.
authors: Johnny X
authors: JX
authors: Huang
authors: Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia.
authors: Mark A
authors: MA
authors: Blaskovich
authors: Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia.
authors: Matthew A
authors: MA
authors: Cooper
authors: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA.
authors: Andres
authors: A
authors: Obregon-Henao
authors: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA.
authors: Ian
authors: I
authors: Orme
authors: School of Animal Biology, The University of Western Australia, Crawley, WA, Australia.
authors: Edwin S
authors: ES
authors: Tjandra
authors: School of Biological Sciences, Flinders University, Bedford Park, SA, Australia.
authors: Uwe H
authors: UH
authors: Stroeher
authors: School of Biological Sciences, Flinders University, Bedford Park, SA, Australia.
authors: Melissa H
authors: MH
authors: Brown
authors: Flinders Medical Science and Technology, Immunology, Allergy and Arthritis, Flinders University, Bedford Park, SA, Australia.
authors: Cindy
authors: C
authors: Macardle
authors: Flinders Medical Science and Technology, Immunology, Allergy and Arthritis, Flinders University, Bedford Park, SA, Australia.
authors: Nick
authors: N
authors: van Holst
authors: Centre for NanoScale Science and Technology, School of Chemical and Physical Sciences, Flinders University, Bedford Park, SA, Australia.
authors: Chee
authors: C
authors: Ling Tong
authors: Centre for NanoScale Science and Technology, School of Chemical and Physical Sciences, Flinders University, Bedford Park, SA, Australia.
authors: Ashley D
authors: 0000000340233506
authors: AD
authors: Slattery
authors: Centre for NanoScale Science and Technology, School of Chemical and Physical Sciences, Flinders University, Bedford Park, SA, Australia.
authors: Christopher T
authors: CT
authors: Gibson
authors: Centre for NanoScale Science and Technology, School of Chemical and Physical Sciences, Flinders University, Bedford Park, SA, Australia.
authors: Colin L
authors: CL
authors: Raston
authors: Centre for NanoScale Science and Technology, School of Chemical and Physical Sciences, Flinders University, Bedford Park, SA, Australia.
authors: Ramiz A
authors: RA
authors: Boulos
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology* / Q000633:toxicity; D017173:Caenorhabditis elegans; D002460:Cell Line; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D040542:Mechanotransduction, Cellular / Q000187:drug effects*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007473:Ion Channels
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