Limitation and future directions

Several limitations of this review should be addressed. Firstly, a small number of studies were included in this review, as only those that reported IC50 values against NDM-1 were considered, which may have excluded mechanistic studies of interest. Secondly, a high degree of assay heterogeneity in the covered studies, substrate selection and experimental conditions complicated the direct comparison of the inhibitory potency. As a result, the use of IC50 values should be approached with caution, as they are not fully standardized across studies. Moreover, most of the collected data are based on in vitro enzyme tests, with little in vivo or clinical confirmation. Another limitation worth mentioning is the inconsistent reporting of stereochemistry, as D/L nomenclature was not accompanied by R/S nomenclature. Lastly, since it is a single-author review, there may be inherent bias in the selection and interpretation process.

Future work must further explore optimization of captopril-derived scaffolds, ranging from balancing hydrophobic capping, fluorination, and thiol masking to enhance stability without compromising zinc-binding ability. Also, adopting consistent reporting with the R/S configuration is recommended to avoid confusion that can result from relying on D/L nomenclature alone. In addition, the assay conditions (e.g. substrates and zinc concentrations) also need to be standardized so that the IC50 values can be compared across studies more reliably. Moreover, clinical translation will be imperative, extending the studies beyond in vitro enzyme assays to in vivo efficacy, pharmacokinetics, and toxicity profiling. The binding interactions will be further elucidated through structural and mechanistic studies, especially by co-crystallization with NDM-1, and then used to design rationally. Lastly, the potential of these inhibitors as adjuvants when used alongside beta-lactam antibiotics should be thoroughly evaluated to address antibiotic resistance in clinical contexts.