According to the CDC, antibiotic resistant infections are one of the leading public health threats of the present day. Four of the six ESKAPE pathogens are Gram-negative bacterial species. The treatment options for infections caused by multi-drug resistant Gram-negative are particularly limited, necessitating the development of novel therapeutic strategies. One means to combatting these infections is to broaden the spectrum of activity of Gram-positive selective antibiotics that are otherwise ineffective against Gram-negative bacteria, most often as a result of limited permeation through the outer membrane. Our approach to this involves the use of small molecule adjuvants that potentiate antibiotic activity. We identified a 2-aminobenzimidzole containing small molecule that enhances the susceptibility of <i>Klebsiella pneumoniae</i> and <i>Acinetobacter baumannii </i>to the macrolide class of antibiotics. Activity has been augmented through the synthesis of a library of derivatives, with the most active compounds effecting reductions in macrolide minimum inhibitory concentration of upwards of 512-fold. Studies to determine the mechanism of action of the small molecule adjuvants are ongoing.

Identification of adjuvants that potentiate macrolide activity against Gram-negative bacteria

ACS Fall 2021

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