A Small-Molecule Inhibitor of -Translation Synergistically Interacts with Cathelicidin Antimicrobial Peptides To Impair Survival of Staphylococcus aureus.

Authors:
Yueyang Huang
Yueyang Huang
Imperial College London
United Kingdom
John N Alumasa
John N Alumasa
Pennsylvania State University University Park
Lauren T Callaghan
Lauren T Callaghan
Texas Christian University
Christopher D Rae
Christopher D Rae
Medical Research Council Laboratory of Molecular Biology
Kenneth C Keiler
Kenneth C Keiler
University Park
United States
Shauna M McGillivray
Shauna M McGillivray
University of California
United States

Antimicrob Agents Chemother 2019 Apr 27;63(4). Epub 2019 Mar 27.

Department of Biology, Texas Christian University, Fort Worth, Texas, USA

is a leading cause of infection in the United States, and due to the rapid development of resistance, new antibiotics are constantly needed. -Translation is a particularly promising antibiotic target because it is conserved in many bacterial species, is critical for bacterial survival, and is unique among prokaryotes. We have investigated the potential of KKL-40, a small-molecule inhibitor of -translation, and find that it inhibits both methicillin-susceptible and methicillin-resistant strains of KKL-40 is also effective against Gram-positive pathogens, including a vancomycin-resistant strain of , , and , although its performance with Gram-negative pathogens is mixed. KKL-40 synergistically interacts with the human antimicrobial peptide LL-37, a member of the cathelicidin family, to inhibit but not other antibiotics tested, including daptomycin, kanamycin, or erythromycin. KKL-40 is not cytotoxic to HeLa cells at concentrations that are 100-fold higher than the effective MIC. We also find that develops minimal resistance to KKL-40 even after multiday passage at sublethal concentrations. Therefore, -translation inhibitors could be a particularly promising drug target against , not only because of their ability to inhibit bacterial growth but also because of their potential to simultaneously render more susceptible to host antimicrobial peptides.

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http://dx.doi.org/10.1128/AAC.02362-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437501PMC
April 2019
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