Triple combination of antibiotics could be the new arsenal against drug-resistant bacteria

In the ongoing battle against antibiotic resistance, a new study published in Engineering by Zhuoren Ling’s research team unveils a promising triple combination of antibiotics that significantly expands our arsenal against drug-resistant bacteria. Titled “The Triple Combination of Meropenem, Avibactam, and a Metallo-β-Lactamase Inhibitor Optimizes Antibacterial Coverage Against Different β-Lactamase Producers,” the research sheds light on a novel approach to tackle one of the most pressing global health challenges of our time.

β-Lactams, a class of antibiotics crucial for treating bacterial infections, have faced mounting resistance due to the emergence of β-lactamase enzymes. These enzymes, including serine-β-lactamases (SBLs) and metallo-β-lactamases (MBLs), render antibiotics ineffective and pose a grave threat to public health. Traditional strategies have focused on modifying antibiotics or utilizing β-lactamase inhibitors like avibactam (AVI). However, the efficacy of these inhibitors is limited against MBLs. The search for MBL inhibitors with broad activity and low toxicity has been challenging. This study investigates a triple combination of meropenem (MEM), a SBLs inhibitor (AVI), and a novel MBL inhibitor (indole carboxylate 58 (InC58)), to overcome antibiotic resistance.

The research team conducted susceptibility testing on a diverse panel of bacteria producing both MBLs and SBLs. Results revealed that the triple combination of MEM, AVI, and InC58 exhibited remarkable efficacy against carbapenemase-producing bacteria, extending the spectrum of activity to strains carrying various β-lactamases, including oxacillinase-48 (OXA-48), Klebsiella pneumoniae carbapenemase-2 (KPC-2), and New Delhi metallo-β-lactamases (NDMs). Notably, this triple combination showed limited effectiveness against certain strains, such as Verona Integron-encoded metallo-β-lactamase (VIM)-carrying Pseudomonas aeruginosa (P. aeruginosa) and OXA-23-carrying Acinetobacter baumannii (A. baumannii).

The study delved into the mechanisms of resistance, the resistance correlated with mutations to ompC and comR, affecting porin C and copper permeability, respectively. The mutants manifested a fitness cost, a decreased level of resistance during passage without antibiotic pressure, and cross resistance to another carbapenem (imipenem) and a β-lactamase inhibitor (taniborbactam).

In conclusion, the triple combination of MEM with InC58 (a novel MBL inhibitor) and AVI (an SBL inhibitor) demonstrates a significantly broader spectrum of antimicrobial activity against diverse β-lactamase-producing bacteria compared to dual combinations. These findings represent a pivotal step forward in the fight against β-lactamase-mediated antimicrobial resistance, offering a new strategy to combat this global health crisis.