FL058, a novel β-lactamase inhibitor, increases the anti-Mycobacterium abscessus activity of imipenem.

Abstract

Background: β-lactams are crucial for anti-Mycobacterium abscessus complex (MABC) therapy. Treating infections is challenging since MABC produces a class A β-lactamase (Bla_Mab) , which is capable of hydrolyzing β-lactams thus causing drug resistance. Diazabicyclooctane (DBO) β-lactamase inhibitors (BLIs) can inhibit Bla_Mab. FL058 is a novel DBO BLI; the anti-MABC activity of FL058 combined with β-lactams remains unknown.

Methods: The activities of ten β-lactams (imipenem, meropenem, faropenem, tebipenem, cefoxitin, cefepime, ceftazidime, cefdinir, cefuroxime, and amoxicillin) combined with three DBO BLIs (FL058, avibactam, and relebactam) toward two MABC reference strains were determined by broth microdilution assay. The anti-MABC activities of imipenem combined with three BLIs against 193 clinical isolates were also evaluated. The activity of imipenem combined with FL058 was also tested against intracellular MABC residing in macrophages and in a mouse model. Finally, the Bla_Mab mutations in clinical isolates were analyzed using sequence alignment to determine whether Bla_Mab mutations are associated with DBO BLIs sensitivity.

Results: FL058, avibactam and relebactam significantly increased the anti-MABC activity of β-lactams, especially imipenem, against reference strains and clinical isolates. The anti-MABC activity of imipenem combined with FL058 was superior to its activity when combined with either avibactam or relebactam. The combination of imipenem and FL058 significantly reduced the numbers of intracellular organisms in cultured macrophages, and of viable bacteria in the lungs of MABC-infected mice. Rough morphotypes tended to be more resistant than smooth morphotype. A Bla_Mab T141A mutation may reduce the susceptibility of MABC to imipenem-BLIs.

Conclusion: The elevated anti-MABC activity exhibited by imipenem combined with FL058 suggests a potential new approach to treating MABC infections.