Structural highlights
FunctionPublication Abstract from PubMedLytic transglycosylases (Lts) are involved in recycling, cell division, and metabolism of the peptidoglycan. They have been understudied for their usefulness as potential antibacterial targets due to their high redundancy in Gram-negative bacteria. Bulgecin A is an O-sulphonated glycopeptide that targets primarily soluble lytic tranglycosylases (Slt). It has been shown that bulgecin A increases the efficacy of beta-lactams that target penicillin bindings proteins (PBPs). Here, we present the high-resolution crystal structure of LtgA from Neisseria meningitidis strain MC58, a membrane bound homolog of Escherichia coli Slt, in complex with bulgecin A. The LtgA-bulgecin A complex reveals the mechanism of inhibition by bulgecin A at near atomic resolution. We further demonstrate that bulgecin A is not only a potent inhibitor of LtgA, but most importantly, it restores the efficacy of beta-lactam antibiotics in strains of N. meningitidis and Neisseria gonorrhoeae that have reduced susceptibility to beta-lactams. This is particularly relevant for N. gonorrhoeae where no vaccines are available. This work illustrates how best to target dangerous pathogens using a multiple drug target approach, a new and alternative approach to fighting antibiotic resistance. Bulgecin A: The Key to a Broad-Spectrum Inhibitor That Targets Lytic Transglycosylases.,Williams AH, Wheeler R, Thiriau C, Haouz A, Taha MK, Boneca IG Antibiotics (Basel). 2017 Feb 22;6(1). pii: E8. doi: 10.3390/antibiotics6010008. PMID:28241458[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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