Biochemical Logic of Antibiotic Inactivation and Modification

Bacteria have evolved a myriad of tactics to circumvent the actions of antibiotics. Bacterial resistance to antibiotics manifests itself in both general and specific protection mechanisms. Consequently, the characteristics of resistance can be paralleled to those of the mammalian immune response. Antibiotic resistance can be differentiated into: (1) nonspecific mechanisms that confer general innate immunity to a class of antibiotics (e.g., broad spectrum efflux mechanisms, target modification) and (2) highly precise responses that include selective enzyme-based mechanisms that mirror the acquired immune response with respect to target specificity and potency. Bacteria deploy both types of mechanisms in response to the presence of cytotoxic antibiotics. One of the most prevalent mechanisms of resistance involves enzymatically altering the antibiotic structure to an inactive derivative, one incapable of acting against its bacterial target. Antibiotic-inactivating enzymes can accomplish this task by one of two means: by eradicating the essential reactive center of the antibiotic or by modifying the drug in a manner that impairs target binding. By critically assessing the manner in which each antibiotic class interacts with its target and the subsequent mode of inactivation, the molecular logic of each strategy can be elucidated.