title: Bulgecin A: The Key to a Broad-Spectrum Inhibitor  That Targets Lytic Transglycosylases.
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.
authors.affiliation: Institut Pasteur, Unité Biologie et génétique de la paroi bactérienne, Dept. Microbiologie, 28 Rue du Dr. Roux, 75015 Paris, France. awilliam@pasteur.fr.|Institut National de la santé et de la Recherche Médicale (INSERM), Groupe Avenir, 75015 Paris, France. awilliam@pasteur.fr.
authors.forename: Allison H
authors.initials: AH
authors.lastname: Williams
authors.affiliation: Institut Pasteur, Unité Biologie et génétique de la paroi bactérienne, Dept. Microbiologie, 28 Rue du Dr. Roux, 75015 Paris, France. richard.wheeler@pasteur.fr.|Institut National de la santé et de la Recherche Médicale (INSERM), Groupe Avenir, 75015 Paris, France. richard.wheeler@pasteur.fr.
authors.forename: Richard
authors.initials: R
authors.lastname: Wheeler
authors.affiliation: Institut Pasteur, Unité Biologie et génétique de la paroi bactérienne, Dept. Microbiologie, 28 Rue du Dr. Roux, 75015 Paris, France. constancethiriau@hotmail.com.|Institut National de la santé et de la Recherche Médicale (INSERM), Groupe Avenir, 75015 Paris, France. constancethiriau@hotmail.com.
authors.forename: Constance
authors.initials: C
authors.lastname: Thiriau
authors.affiliation: Institut Pasteur, CNRS-UMR3528, Plate-forme de Cristallographie, 25 Rue Dr. Roux, 75724 Paris, France. ahmed.haouz@pasteur.fr.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Haouz
authors.affiliation: Institut Pasteur, Unité des Infection Bactériennes Invasives, Dept. Infection et Epidémiologie, 28 Rue du Dr. Roux, 75015 Paris, France. mktaha@pasteur.fr.
authors.forename: Muhamed-Kheir
authors.initials: MK
authors.lastname: Taha
authors.affiliation: Institut Pasteur, Unité Biologie et génétique de la paroi bactérienne, Dept. Microbiologie, 28 Rue du Dr. Roux, 75015 Paris, France. bonecai@pasteur.fr.|Institut National de la santé et de la Recherche Médicale (INSERM), Groupe Avenir, 75015 Paris, France. bonecai@pasteur.fr.
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Boneca
keywords: peptidoglycan;  Neisseria;  beta‐lactam;  bulgecin;  lytic transglycosylase