Inhibiting Mycobacterium abscessus Cell Wall Synthesis: Using a Novel Diazabicyclooctane β-Lactamase Inhibitor To...

Area of Science:

• Microbiology
• Pharmacology
• Biochemistry

Background:

• Mycobacterium abscessus infections pose a significant threat, particularly to individuals with cystic fibrosis and structural lung disease.
• Multidrug resistance is common in M. abscessus, necessitating novel therapeutic strategies.
• Understanding peptidoglycan synthesis is key to developing effective treatments.

Purpose of the Study:

• To evaluate durlobactam (DUR), a novel β-lactamase inhibitor, in combination with β-lactams against M. abscessus.
• To provide a biochemical rationale for the activity of DUR in M. abscessus treatment.
• To identify potent β-lactam and β-lactamase inhibitor combinations for M. abscessus infections.

Main Methods:

• In vitro susceptibility testing of M. abscessus isolates with various β-lactam and durlobactam combinations.
• Biochemical assays to determine durlobactam's inhibition of β-lactamase BlaMab.
• Mass spectrometry to analyze durlobactam's interaction with M. abscessus enzymes.
• Molecular modeling to elucidate durlobactam's binding mechanisms.

Main Results:

• Durlobactam significantly enhanced the susceptibility of M. abscessus to amoxicillin, imipenem, and cefuroxime.
• The triple drug combinations of cefuroxime-durlobactam-amoxicillin and imipenem-durlobactam-amoxicillin showed potent activity (MIC ≤ 1 μg/mL).
• Durlobactam potently inhibited BlaMab and formed stable complexes with LdtMab2-4 and M. abscessus d,d-carboxypeptidase.

Conclusions:

• Durlobactam protects amoxicillin and imipenem from hydrolysis by BlaMab.
• Durlobactam exhibits intrinsic activity by targeting multiple cell wall synthesis enzymes.
• The combination of durlobactam with β-lactams offers a promising therapeutic approach for M. abscessus infections.