Carbapenems are an effective treatment for many life-threatening infections, but unfortunately, carbapenem-resistant enterobacteria (CRE) are on the rise and the mechanisms that lead to this resistance are still under study. A timely diagnosis of potential CRE could favour more effective treatment lines and avoid the spread of resistance. Typically, CRE are identified because they are carbapenemase producers, however, there are other mechanisms that contribute to this resistance. In a recent study, using Klebsiella pneumoniae, we revealed that a major contribution to CRE comes from the combined effect of beta-lactamases potentiated by modifications of outer membrane proteins. Here I will describe the bioinformatic strategies and methodologies to identify these different resistance mechanisms, and discuss these methods’ contributions to control these infections and understand their spread. Furthermore, I will extend on how these methods are applicable in a metagenomics context for a broader diagnosis and understanding of resistance in bacteria.