Introduction: Carbapenem antibiotics are among the most powerful treatments available for multidrug-resistant Gram-negative bacterial infections, serving as the "last line of defense" in many clinical settings. However, the rise of carbapenem-resistant bacteria has emerged as a critical public health challenge worldwide. The mechanisms driving this resistance are multifaceted, including the production of carbapenem-hydrolyzing enzymes, alterations in membrane permeability, increased efflux pump activity, and modifications to drug-binding targets. This review summarizes the molecular mechanisms of carbapenem resistance and explores innovative strategies to combat these threats, aiming to provide a comprehensive approach to mitigate the impact of resistant pathogens.
Methods: This review is based on a systematic examination of recent literature sourced from major databases, including PubMed, Scopus, and Google Scholar, using key terms such as “carbapenem resistance,” “mechanisms of resistance,” and “novel therapeutic strategies.” Studies focusing on the molecular mechanisms underlying resistance in Gram-negative bacteria and the development of new treatment modalities were analyzed. In particular, the review emphasizes the resistance profiles of Pseudomonas aeruginosa and Acinetobacter baumannii, which are among the most clinically relevant pathogens exhibiting carbapenem resistance.
Results: The review identifies several primary mechanisms by which Gram-negative bacteria exhibit resistance to carbapenems:
Carbapenemase Production
The production of carbapenemases, such as KPC, NDM, OXA, and VIM, is the leading cause of carbapenem resistance. These enzymes break down carbapenems, preventing the drug from exerting its antibacterial effect. Carbapenemase genes are often located on plasmids, which facilitate rapid horizontal gene transfer between bacteria.
Altered Outer Membrane Permeability
Changes in outer membrane proteins, including porins like OmpK35 and OmpK36 in Klebsiella pneumoniae, lead to reduced drug influx into bacterial cells, enhancing resistance. This reduction in membrane permeability serves as a significant barrier to antibiotic action.
Efflux Pump Overexpression
Efflux pumps actively expel carbapenem molecules from the bacterial cell, maintaining sublethal concentrations of the drug within the bacteria and thus contributing to resistance. Overexpression of these pumps significantly lowers the intracellular concentration of antibiotics, rendering them less effective.
Target Site Modification
While less common, structural alterations in penicillin-binding proteins (PBPs) reduce carbapenem binding affinity, contributing to resistance. These modifications prevent the drug from interacting effectively with its target site within the bacterial cell wall.
In clinically significant pathogens like Pseudomonas aeruginosa and Acinetobacter baumannii, resistance is often compounded by the co-expression of multiple resistance mechanisms, making treatment more challenging and contributing to the failure of conventional therapeutic approaches.
Conclusion: Carbapenem resistance in Gram-negative bacteria is a rapidly growing threat to global public health, underscoring the need for urgent intervention. To address this, a comprehensive strategy is essential, combining a deep understanding of the molecular mechanisms of resistance with innovative therapeutic approaches. New β-lactam/β-lactamase inhibitor combinations and advanced drug delivery systems, such as nanotechnology-based platforms, offer promising solutions to enhance the efficacy of existing antibiotics. Additionally, next-generation antibiotics tailored to target specific resistance mechanisms hold great potential. Ongoing research and international collaboration are critical to developing sustainable strategies to curb the spread of carbapenem resistance and protect the effectiveness of these vital drugs.