Kibdelomycin Is a Bactericidal Broad-Spectrum Aerobic Antibacterial Agent

Abstract

ABSTRACTBacterial resistance to antibiotics continues to grow and pose serious challenges, while the discovery rate for new antibiotics declines. Kibdelomycin is a recently discovered natural-product antibiotic that inhibits bacterial growth by inhibiting the bacterial DNA replication enzymes DNA gyrase and topoisomerase IV. It was reported to be a broad-spectrum aerobic Gram-positive agent with selective inhibition of the anaerobic bacteriumClostridium difficile. We have extended the profiling of kibdelomycin by using over 196 strains of Gram-positive and Gram-negative aerobic pathogens recovered from worldwide patient populations. We report the MIC50s, MIC90s, and bactericidal activities of kibdelomycin. We confirm the Gram-positive spectrum and report for the first time that kibdelomycin shows strong activity (MIC90, 0.125 μg/ml) against clinical strains of the Gram-negative nonfermenterAcinetobacter baumanniibut only weak activity againstPseudomonas aeruginosa. We confirm that well-characterized resistant strains ofStaphylococcus aureusandStreptococcus pneumoniaeshow no cross-resistance to kibdelomycin and quinolones and coumarin antibiotics. We also show that kibdelomycin is not subject to efflux inPseudomonas, though it is inEscherichia coli, and it is generally affected by the outer membrane permeability entry barrier in the nonfermentersP. aeruginosaandA. baumannii, which may be addressable by structure-based chemical modification.