In 2016, the World Health Organization deemed antibiotic resistance one of the biggest threats to global health, food security, and development due to the increasing prevalence of resistance but decreasing effectiveness of antibiotic treatment. While development of new antibiotics remains an option to overcome increasing resistance, another option is the use of an antibiotic adjuvant to overcome the intrinsic resistance mechanisms of the bacteria so that existing antibiotics are still effective. Despite the capability adjuvants have to overcome resistance mechanisms, their ability to sensitize Gram-negative bacteria to Gram-positive selective antibiotics has been minimally explored. We have identified two lead compounds, which are capable of potentiating Gram-positive selective antibiotics, including macrolides and glycopeptides, against the Gram-negative bacterium Acinetobacter baumannii. Initial mode of action studies reveal that these adjuvants likely work through disruption of lipopolysaccharide synthesis or assembly. Furthermore, the effectiveness of the lead compound to potentiate clarithromycin in vivo was tested using a Galleria mellonella model of an A. baumannii infection, and the combination therapy showed increased survival of G. mellonella.

Small molecule potentiation of Gram-positive selective antibiotics against Gram-negative Acinetobacter baumannii

255th National Meeting (2018)

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