In Vitro Activity of β-Lactams in Combination with β-Lactamase Inhibitors against Mycobacterium tuberculosis Clinical Isolates

Abstract

Objectives Evaluating the activity of nineteen β-lactams in combination with different β-lactamase inhibitors to determine the most potent combination against Mycobacterium tuberculosis (MTB) in vitro. Methods Drug activity was examined by drug susceptibility test with 122 clinical isolates from China. Mutations of blaC and drug targets ldtMt1, ldtMt2, dacB2, and crfA were analyzed by nucleotide sequencing. Results Tebipenem (TBM) in combination with clavulanate (CLA) exhibited the highest anti-TB activity. The MIC of β-lactam antibiotics was reduced most evidently in the presence of CLA, compared to avibactam (AVI) and sulbactam (SUB). Eight polymorphism sites were identified in blaC, which were not associated with β-lactams resistance. Interestingly, one strain carrying G514A mutation in blaC was highly susceptible to β-lactams regardless of the presence of inhibitors. The transpeptidase encoding genes, ldtMt1, ldtMt2, and dacB2, harboured three mutations, two mutations, and one mutation, respectively, but no correlation was found between these mutations and drug resistance. Conclusion The activity of β-lactams against MTB and different synergetic effect of β-lactamase inhibitors were indicated. TBM/CLA exhibited the most activity and has a great prospect in developing novel anti-TB regimen; however, further clinical research is warranted. Moreover, the resistance to the β-lactam antibiotics might not be conferred by single target mutation in MTB and requires further studies.

Synthesis and recycling of the mycobacterial cell envelope

“…This intensive research highlights the importance of these enzymes, particularly from the perspective of inhibitor discovery [ 9 , 10 , 16 , 19 ]. Classical transpeptidation by Penicillin Binding Proteins (PBPs) has also received renewed interest, especially since the validated inhibition of the β-lactamase, BlaC [ 20 , 21 , 22 , 23 ], which has re-established the potential of β-lactam antibiotics as a treatment for TB [ 24 , 25 ]. Many PBPs have redundant roles in vitro , however, they have critical roles for survival and virulence within the host.…”

Discovery of beta-lactamase CMY-10 inhibitors for combination therapy against multi-drug resistant Enterobacteriaceae

“…Various research studies have reported the efficacy of using a combination of β-lactam antibiotic with β-lactamase inhibitor in enhancing the potency of antibacterial agents [1,22,23]. In the current study, MICs were also determined using computationally screened inhibitors in combination with cefixime against MDR clinical isolates to exploit the strategy of combination therapeutics.…”

N-Thio-β-lactams targeting L,D-transpeptidase-2, with activity against drug-resistant strains of Mycobacterium tuberculosis

“…Five 2-fold serial dilutions were prepared starting from stock solutions resulting the final concentrations of 2.5, 5, 10, 20, and 40 mg/mL. Clavulanic acid was added at a final concentration of 5 mg/mL (Li et al, 2018;Diacon et al, 2016). Colonies (3 to 5) of the tested strains were picked from LJ slants and adjusted in a Saline Tween with Glass Beads solution (Thermo ScientificÔUSA) to 1.5 x 10 8 CFU/mL (0.5 Mc Farland).…”