Pharmacochemical Evolution of Carbapenems and Structural Analogues

Abstract

Carbapenems are a major class of antibiotics with a β-lactam nucleus that are distinguished by their effectiveness against many resistant pathogens. The discovery of Thienamycin, from Streptomyces cattleya, was the starting point for these antibiotics that revolutionized the treatment of serious infections thanks to their broad spectrum and stability in the face of various β-lactamases. This work aims to describe the pharmacochemical advances of carbapenems, the structural modifications undertaken as well as their physicochemical and pharmacotherapeutic properties. A systematic review was carried out, drawing on scientific publications, specialized manuals, and databases. Research has focused on the mechanisms of action, structural modifications, and biological properties of carbapenems, with a focus on recent innovations to improve chemical stability, broaden the antibacterial spectrum and counter bacterial resistance. Thienamycin, while promising, presented challenges for its clinical exploitation, due to its low chemical stability. This led to the synthesis of more stable semi-synthetic derivatives, such as Imipenem, the first carbapenem used in the clinic. The combination of Imipenem and Cilastatin, a dehydropeptidase-1 inhibitor, has circumvented the metabolic limitations associated with Imipenem, enhancing its therapeutic efficacy. Successive advances have given rise to other carbapenems, such as Meropenem, Doripenem, Ertapenem, Sulopenem, Faropenem, characterized by better pharmacokinetics and a broad spectrum. Their development is based on precise structural modifications, aimed at maximizing their chemical stability, bacterial efficacy while minimizing side effects and bacterial resistance. Faced with the emergence of multi-resistant pathogens, research on carbapenems remains a crucial axis. The improvement of hemi-synthesis strategies and the exploration of new therapeutic combinations open up promising prospects for combating current infectious threats.Carbapenems illustrate advances in therapeutic chemistry in the fight against resistant infections. However, the emergence of new resistances, such as those related to carbapenemases, requires constant innovation. Future generations of carbapenems will need to rely on targeted modifications to broaden their spectrum while reducing the risk of side effects.