Durlobactam in combination with β-lactams to combat Mycobacterium abscessus

• Published in: Antimicrobial agents and chemotherapy 2024-12, p.e0117424
• Main Authors: Shin, Eunjeong, Dousa, Khalid M, Taracila, Magdalena A, Bethel, Christopher R, Nantongo, Mary, Nguyen, David C, Akusobi, Chidiebere, Kurz, Sebastian G, Plummer, Mark S, Daley, Charles L, Holland, Steven M, Rubin, Eric J, Bulitta, Jürgen B, Boom, W Henry, Kreiswirth, Barry N, Bonomo, Robert A
• Format: Article
• Language: English
• Subjects: Antimicrobial Chemotherapy; Clinical Therapeutics
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/aac.01174-24

( ) presents significant clinical challenges. This study evaluated the synergistic effects of a β-lactam and β-lactamase inhibitor combination against and explored the underlying mechanisms. Synergy was assessed through MIC tests and time-kill studies, and binding affinities of nine β-lactams and BLIs to eight target receptors (L,D-transpeptidases [LDT] 1-5, D,D-carboxypeptidase, penicillin-binding protein [PBP] B, and PBP-lipo) were assessed using mass spectrometry and kinetic studies. Thermal stability and morphological changes were determined. Imipenem demonstrated high binding affinity to LDTs and PBPs, with extremely low inhibition constants ( ; ≤0.002 mg/L for LDT1-2, ≤0.6 mg/L for PBPs), while cephalosporins, sulopenem, tebipenem, and amoxicillin exhibited moderate to low binding affinity. Durlobactam inactivated Bla and LDT/PBPs more potently than avibactam. The s of durlobactam for PBP B, PBP-lipo, and LDT2 were below clinically achievable unbound concentrations, while avibactam's for LDT/PBPs exceeded the clinical concentrations. Single β-lactam treatments resulted in minimal killing (~1 log reduction). Although avibactam yielded no effect, combinations with avibactam showed a significant reduction (~4 log CFU/mL). Durlobactam alone showed ~2 log reduction, and when combined with imipenem or two β-lactams, durlobactam achieved near-eradication of , surpassing the current therapy (amikacin + clarithromycin + imipenem/cefoxitin). Inactivation of PBP-lipo by sulopenem, imipenem, durlobactam, and amoxicillin (with avibactam) led to morphological changes, showing filaments. This study demonstrates the mechanistic basis of combinations therapy, particularly imipenem + durlobactam, in overcoming β-lactam resistance in .