Apramycin Overcomes the Inherent Lack of Antimicrobial Bactericidal Activity in Mycobacterium abscessus

• Published in: Antimicrobial agents and chemotherapy Vol. 66; no. 2; p. e0151021
• Main Authors: Selchow, Petra, Ordway, Diane J, Verma, Deepshikha, Whittel, Nicholas, Petrig, Aline, Hobbie, Sven N, Böttger, Erik C, Sander, Peter
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 15.02.2022
• Subjects: Antimicrobial Chemotherapy; Susceptibility; aminoglycoside; antibiotic treatment; pulmonary disease; cystic fibrosis; apramycin; bactericidal activity; drug resistance; Mycobacterium abscessus
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/aac.01510-21

Antibiotic therapy of infections caused by the emerging pathogen Mycobacterium abscessus is challenging due to the organism's inherent resistance to clinically available antimicrobials. The low bactericidal potency of currently available treatment regimens is of concern and testifies to the poor therapeutic outcomes for pulmonary M. abscessus infections. Mechanistically, we demonstrate here that the acetyltransferase Eis2 is responsible for the lack of bactericidal activity of amikacin, the standard aminoglycoside used in combination treatment. In contrast, the aminoglycoside apramycin, with a distinct structure, is not modified by any of the pathogen's innate aminoglycoside resistance mechanisms and is not affected by the multidrug resistance regulator WhiB7. As a consequence, apramycin uniquely shows potent bactericidal activity against M. abscessus. This favorable feature of apramycin is reflected in a mouse model of pulmonary M. abscessus infection, which demonstrates superior activity, compared with amikacin. These findings encourage the development of apramycin for the treatment of M. abscessus infections and suggest that M. abscessus eradication in pulmonary disease may be within therapeutic reach.