A new antimicrobial agent, known as ADC56, has shown efficacy and selectivity in vitro and in vivo against Gram-negative pathogens, according to research presented at American Society for Microbiology (ASM) Microbe 2019, held June 20 to 24, 2019 in San Francisco, California.

Actinomycetes have been overmined as the main source of antibiotics; therefore, researchers explored Photorhabdus, entomopathogenic bacteria that are symbionts of nematodes that infect insects and inject them with an antibiotic that prevents infection in that host from other pathogens. The researchers screened 63 Photorhabdus strains against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus and found that 1 of the Photorhabdus-injected extracts showed potent activity.

The extract was fractionated by high-performance liquid chromatography, and the active fraction was detected by a bioactivity-guided assay. A combination of liquid chromatography-mass spectrometer and nuclear magnetic resonance spectroscopy made clear the structure of the active compound, named ADC56, which is a ribosomally synthesized and post-translationally modified peptide with a unique scaffold made of 2 rings with unusual linker bonds.

ADC56 showed effective antibiotic concentrations in vitro against Gram-negative pathogens, such as E coli (minimal inhibitory concentration [MIC], 4 µg/mL), P aeruginosa (MIC, 2 µg/mL), Klebsiella pneumoniae (MIC, 2 µg/mL), and Acinetobacter baumannii (MIC, 8 µg/mL).

Researchers noted that although ADC56 lacked activity against Gram-positive and Gram-negative Bacteroides, important Gram-negative members of the gut microbiota, it was effective against colistin-resistant E coli AR350 (MIC, 2 µg/mL) and did not bind to lipopolysaccharide.

Researchers further investigated ADC56 efficacy against E coli and P aeruginosa, including colistin-resistant mutants in a mouse septicemia model, and demonstrated success against colistin-resistant E coli in a mouse thigh model.

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“ADC56 is a promising lead for combating Gram-negative [multidrug resistant] infections without harming our gut symbionts,” concluded the researchers.

Reference

Imai K, Meyer KJ, Favre-Godal Q, et al. ADC56 is a novel antimicrobial acting against gram-negative pathogen. Presented at: ASM Microbe 2019; June 20-24, 2019; San Francisco, CA. Poster P589.