Bulgecin A: The Key to a Broad‐Spectrum Inhibitor That Targets Lytic Transglycosylases

Allison Williams,Muhamed‐Kheir Taha,Ivo Boneca,Richard Wheeler,Constance Thiriau,Ahmed Haouz

doi:10.3390/antibiotics6010008

Allison Williams, Muhamed‐Kheir Taha + Show 4 more

Open Access

https://doi.org/10.3390/antibiotics6010008

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Abstract

Lytic 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 β-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 β-lactam antibiotics in strains of N. meningitidis and Neisseria gonorrhoeae that have reduced susceptibility to β-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.

Highlights

Institut Pasteur, CNRS-UMR3528, Plate-forme de Cristallographie, 25 Rue Dr Roux, 75724 Paris, France; Institut Pasteur, Unité des Infection Bactériennes Invasives, Dept
Current dogma suggests that β-lactams, the most widely used class of antibiotic, disrupt the delicate balance that occurs between penicillin binding proteins (PBPs) and lytic transglycosylases (Lts) [3]
We demonstrate that bulgecin A, combined with β-Lactams, could be a useful alternative strategy for restoring the efficacy of β-lactams in resistant strains of N. meningitidis and N. gonorrhoeae

Summary

Introduction

Institut Pasteur, CNRS-UMR3528, Plate-forme de Cristallographie, 25 Rue Dr Roux, 75724 Paris, France; Institut Pasteur, Unité des Infection Bactériennes Invasives, Dept. We further demonstrate that bulgecin A is a potent inhibitor of LtgA, but most importantly, it restores the efficacy of β-lactam antibiotics in strains of N. meningitidis and Neisseria gonorrhoeae that have reduced susceptibility to β-lactams. This is 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 It has been clear since the 1960s that treatment of bacterial infections with β-lactams has given rise to highly resistant bacteria. This success is threatened by the alarming rise of resistance to β-lactam antibiotics

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