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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.

Human glucose-dependent insulinotropic polypeptide (GIP) is an antimicrobial adjuvant re-sensitising multidrug-resistant Gram-negative bacteria