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Upregulation of PBP1B and LpoB in cysB Mutants Confers Mecillinam (Amdinocillin) Resistance in Escherichia coli
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0001-6640-2174
2019 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 63, no 10, article id e00612-19Article in journal (Refereed) Published
Abstract [en]

Mecillinam (amdinocillin) is a beta-lactam antibiotic that inhibits the essential penicillin-binding protein 2 (PBP2). In clinical isolates of Escherichia coli from urinary tract infections, inactivation of the cysB gene (which encodes the main regulator of cysteine biosynthesis, CysB) is the major cause of resistance. How a nonfunctional CysB protein confers resistance is unknown, however, and in this study we wanted to examine the mechanism of resistance. Results show that cysB mutations cause a gene regulatory response that changes the expression of similar to 450 genes. Among the proteins that show increased levels are the PBP1B, LpoB, and FtsZ proteins, which are known to be involved in peptidoglycan biosynthesis. Artificial overexpression of either PBP1B or LpoB in a wild-type E. coli strain conferred mecillinam resistance; conversely, inactivation of either the mrcB gene (which encodes PBP1B) or the IpoB gene (which encodes the PBP1B activator LpoB) made cysB mutants susceptible. These results show that expression of the proteins PBP1B and LpoB is both necessary and sufficient to confer mecillinam resistance. The addition of reducing agents to a cysB mutant converted it to full susceptibility, with associated downregulation of PBP1B, LpoB, and FtsZ. We propose a model in which cysB mutants confer mecillinam resistance by inducing a response that causes upregulation of the PBP1B and LpoB proteins. The higher levels of these two proteins can then rescue cells with mecillinam-inhibited PBP2. Our results also show how resistance can be modulated by external conditions such as reducing agents.

Place, publisher, year, edition, pages
2019. Vol. 63, no 10, article id e00612-19
Keywords [en]
Escherichia coli, amdinocillin, antibiotic resistance, cell wall, cysB, cysteine, ftsZ, IpoB, mechanisms of resistance, mecillinam, penicillin-binding protein, redox state
National Category
Microbiology in the medical area Microbiology
Identifiers
URN: urn:nbn:se:uu:diva-395783DOI: 10.1128/AAC.00612-19ISI: 000487320100076PubMedID: 31332059OAI: oai:DiVA.org:uu-395783DiVA, id: diva2:1366204
Funder
Swedish Research CouncilAvailable from: 2019-10-28 Created: 2019-10-28 Last updated: 2019-10-28Bibliographically approved

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