Abstract
Increasing antibiotic resistance in Gram-negative bacteria has mandated the development of both novel antibiotics and alternative therapeutic strategies. Evidence of interplay between several gastrointestinal peptides and the gut microbiota led us to investigate potential and broad-spectrum roles for the incretin hormone, human glucose-dependent insulinotropic polypeptide (GIP) against the Enterobacteriaceae bacteria, Escherichia coli and Erwinia amylovora. GIP had a potent disruptive action on drug efflux pumps of the multidrug resistant bacteria E. coli TG1 and E. amylovora 1189 strains. The effect was comparable to bacterial mutants lacking the inner and outer membrane efflux pump factor proteins AcrB and TolC. While GIP was devoid of direct antimicrobial activity, it has a potent membrane depolarizing effect, and at low concentrations, it significantly potentiated the activity of eight antibiotics and bile salt by reducing MICs by 4-8-fold in E. coli TG1 and 4-20-fold in E. amylovora 1189. GIP can thus be regarded as an antimicrobial adjuvant with potential for augmenting the available antibiotic arsenal.
Funding source: Australian Research Council
Award Identifier / Grant number: DP160101312
Award Identifier / Grant number: LE200100163
Funding source: National Health and Medical Research Council
Award Identifier / Grant number: APP1142472
Award Identifier / Grant number: APP1158841
Award Identifier / Grant number: APP1185426
Award Identifier / Grant number: APP1117483
Funding source: Scientific Research Support Fund of Jordan
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Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
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Research funding: The authors gratefully acknowledge the financial support by Scientific Research Support Fund of Jordan (SRSF). Eng. Rakeen Abuhanih (GMA Jordan) is thanked for the helpful discussions and careful proofreading. The authors would also like to thank Jordan Center for Pharmaceutical Research (JCPR) for their help in mass spectrometry (MS) measurements. The National Health and Medical Research Council (NHMRC) of Australia and Australian Research Council (ARC) are thanked for financial support over many years for the peptide chemistry and chemical biology studies reported in the authors’ laboratories. NMOS is the recipient of NHMRC funding (APP1142472, APP1158841, APP1185426), ARC funding (DP160101312, LE200100163), Cancer Council Victoria funding (APP1163284) and Australian Dental Research Funding in antimicrobial materials and research is supported by the Centre for Oral Health Research at The Melbourne Dental School. JDW is an NHMRC Principal Research Fellow (APP1117483). The studies undertaken in his laboratory was supported by an NHMRC Project grant (APP1158841). WL is the recipient of the 2019 Weary Dunlop Foundation grant and 2020 Early Career Researcher grant scheme of the University of Melbourne. Research at The Florey Institute of Neuroscience and Mental Health is supported by the Victorian Government Operational Infrastructure Support Program.
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Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
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The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2020-0351).
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