title: Sub-inhibitory cefsulodin sensitization of E. coli to β-lactams is mediated by PBP1b inhibition.
abstract: The combination of antibiotics is one of the strategies to combat drug-resistant bacteria, though only a handful of such combinations are in use, such as the β-lactam combinations. In the present study, the efficacy of a specific sub-inhibitory concentration of cefsulodin with other β-lactams was evaluated against a range of Gram-negative clinical isolates. This approach increased the sensitivity of the isolates, regardless of the β-lactamase production. The preferred target and mechanism of action of cefsulodin were identified in laboratory strains of Escherichia coli, by examining the effects of deleting the penicillin-binding protein (PBP) 1a and 1b encoding genes individually. Deletion of PBP1b was involved in sensitizing the bacteria to β-lactam agents, irrespective of its O-antigen status. Moreover, the use of a sub-inhibitory concentration of cefsulodin in combination with a β-lactam exerted an effect similar to that one obtained for PBP1b gene deletion. We conclude that the identified β-lactam/cefsulodin combination works by inhibiting PBP1b (at least partially) despite the involvement of β-lactamases, and therefore could be extended to a broad range of Gram-negative pathogens.
authors.affiliation: Department of Biotechnology, Indian Institute of Technology, Kharagpur, West Bengal, India.
authors.forename: Sujoy K
authors.initials: SK
authors.lastname: Sarkar
authors.forename: Mouparna
authors.initials: M
authors.lastname: Dutta
authors.forename: Akash
authors.initials: A
authors.lastname: Kumar
authors.forename: Dhriti
authors.initials: D
authors.lastname: Mallik
authors.forename: Anindya S
authors.initials: AS
authors.lastname: Ghosh
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002441:Cefsulodin / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects* / Q000276:immunology / Q000302:isolation & purification; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005453:Fluorescence; D017353:Gene Deletion; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D019081:O Antigens / Q000378:metabolism; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D046928:Peptidoglycan Glycosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D019081:O Antigens; D046915:Penicillin-Binding Proteins; D046928:Peptidoglycan Glycosyltransferase; C478681:penicillin-binding protein 1B, E coli; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase; D001618:beta-Lactamases; D002441:Cefsulodin