Exploring strategies to combat antibiotic resistance

Understanding antibiotic resistance

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. This research sheds light on a novel approach to tackle one of the most pressing global health challenges of our time.

The role of β-lactams and resistance

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).

Advancements in antibiotic combinations

The 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).

Challenges and limitations

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).

Conclusion

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.

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