715. Bulgecin A lowers Imipenem MICs in Clinical MDR Acinetobacter baumannii (ACB) Strains

Abstract

BackgroundGenetic screening of ACB has revealed genes that confer increased susceptibility to β-lactams when these genes are disrupted suggesting novel drug targets. One such target is lytic transglycosylase, LT. Bulgecin A (BlgA) is a natural product of Paraburkholderia acidophila and an LT inhibitor that potentiates the activity of β-lactams.MethodsBroth microdilution MICs were performed using carbapenem-resistant (CR)-colisitin susceptible (ColS) and CR-ColR clinical ACB strains, with a variety of resistance mechanisms, previously studied via whole-genome sequencing. A fixed concentration of pure BlgA at 100 μg/mL was combined with varying concentrations of imipenem. Sequences of the putative LTs in ACB strains were analyzed to look for amino-acid substitutions and correlated with the MIC lowering effect of BlgA. Homology models of the LTs of AB0057 ACB strain were generated.ResultsACB MltE most resembles soluble LTs of other species with 22.39% sequence identity and 92% query coverage to Slt70 of E. coli. MIC results and amino-acid sequence variations in MltE LT of ACB are shown. There were no clear amino-acid substitution patterns to account for differences in BlgA effect. The mutations are distal to the BlgA binding site at residue E506.ConclusionThese are the first MICs reported for BlgA in combination with a carbapenem demonstrating reduction in the MIC by four-fold for several MDR ACB clinical strains. Mutations in MltE Lt do not account for variations in the MICs observed. Changes in the MICs may be related to other factors such as drug penetration and alterations in PBP expression. Additional studies are underway to examine these factors. Disclosures All authors: No reported disclosures.