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AR-12 Exhibits Direct and Host-Targeted Antibacterial Activity toward Mycobacterium abscessus.

ABSTRACT: Therapeutic options for Mycobacterium abscessus infections are extremely limited. New or repurposed drugs are needed. The anti-M. abscessus activity of AR-12 (OSU-03012), reported to express broad-spectrum antimicrobial effects, was investigated in vitro and in vivo Antimicrobial susceptibility testing was performed on 194 clinical isolates. Minimum bactericidal concentration and time-kill kinetics assays were conducted to distinguish the bactericidal versus bacteriostatic activity of AR-12. Synergy between AR-12 and five clinically important antibiotics was determined using a checkerboard synergy assay. The activity of AR-12 against intracellular M. abscessus residing within macrophage was also evaluated. Finally, the potency of AR-12 in vivo was determined in a neutropenic mouse model that mimics pulmonary M. abscessus infection. AR-12 exhibited high anti-M. abscessus activity in vitro, with an MIC50 of 4?mg/liter (8.7??M) and an MIC90 of 8?mg/liter (17.4??M) for both subsp. abscessus and subsp. massiliense AR-12 and amikacin exhibited comparable bactericidal activity against extracellular M. abscessus in culture. AR-12, however, exhibited significantly greater intracellular antibacterial activity than amikacin and caused a significant reduction in the bacterial load in the lungs of neutropenic mice infected with M. abscessus No antagonism between AR-12 and clarithromycin, amikacin, imipenem, cefoxitin, or tigecycline was evident. In conclusion, AR-12 is active against M. abscessus in vitro and in vivo and does not antagonize the most frequently used anti-M. abscessus drugs. As such, AR-12 is a potential candidate to include in novel strategies to treat M. abscessus infections.

SUBMITTER: Zhang S

PROVIDER: S-EPMC7526805 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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AR-12 Exhibits Direct and Host-Targeted Antibacterial Activity toward Mycobacterium abscessus.

Zhang Shaoyan S Zou Yuzhen Y Guo Qi Q Chen Jianhui J Xu Liyun L Wan Xiaoyu X Zhang Zhemin Z Li Bing B Chu Haiqing H

Antimicrobial agents and chemotherapy 20200722 8

Therapeutic options for Mycobacterium abscessus infections are extremely limited. New or repurposed drugs are needed. The anti-M. abscessus activity of AR-12 (OSU-03012), reported to express broad-spectrum antimicrobial effects, was investigated in vitro and in vivo Antimicrobial susceptibility testing was performed on 194 clinical isolates. Minimum bactericidal concentration and time-kill kinetics assays were conducted to distinguish the bactericidal versus bacterios ...[more]

PMID: 32482678

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Project description:Mycobacterium abscessus is a rapid growing, free-living species of bacterium that also causes lung infections in humans. Human infections are usually acquired from the environment; however, dominant circulating clones (DCCs) have emerged recently in both M. abscessus subsp. massiliense and subsp. abscessus that appear to be transmitted among humans and are now globally distributed. These recently emerged clones are potentially informative about the ecological and evolutionary mechanisms of pathogen emergence and host adaptation. The geographical distribution of DCCs has been reported, but the genomic processes underlying their transition from environmental bacterium to human pathogen are not well characterized. To address this knowledge gap, we delineated the structure of M. abscessus subspecies abscessus and massiliense using genomic data from 200 clinical isolates of M. abscessus from seven geographical regions. We identified differences in overall patterns of lateral gene transfer (LGT) and barriers to LGT between subspecies and between environmental and host-adapted bacteria. We further characterized genome reorganization that accompanied bacterial host adaptation, inferring selection pressures acting at both genic and intergenic loci. We found that both subspecies encode an expansive pangenome with many genes at rare frequencies. Recombination appears more frequent in M. abscessus subsp. massiliense than in subsp. abscessus, consistent with prior reports. We found evidence suggesting that phage are exchanged between subspecies, despite genetic barriers evident elsewhere throughout the genome. Patterns of LGT differed according to niche, with less LGT observed among host-adapted DCCs versus environmental bacteria. We also found evidence suggesting that DCCs are under distinct selection pressures at both genic and intergenic sites. Our results indicate that host adaptation of M. abscessus was accompanied by major changes in genome evolution, including shifts in the apparent frequency of LGT and impacts of selection. Differences were evident among the DCCs as well, which varied in the degree of gene content remodelling, suggesting they were placed differently along the evolutionary trajectory toward host adaptation. These results provide insight into the evolutionary forces that reshape bacterial genomes as they emerge into the pathogenic niche.

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AR-12 Exhibits Direct and Host-Targeted Antibacterial Activity toward Mycobacterium abscessus.

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AR-12 Exhibits Direct and Host-Targeted Antibacterial Activity toward <i>Mycobacterium abscessus</i>.

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