Bacterial proteases: current therapeutic use and future prospects for the development of new antibiotics

Abstract

Proteases of the serine-, cysteine- and metallo- type are widely spread in many pathogenic bacteria, where they play critical functions related to colonisation and evasion of host immune defences, acquisition of nutrients for growth and proliferation, facilitation of dissemination, or tissue damage during infection. Since all the antibiotics currently used clinically share a common mechanism of action, i.e., inhibition of bacterial cell wall biosynthesis, resistance to these pharmacological agents represents a serious medical problem, which might be resolved by using a new generation of antibiotics with a different mechanism of action. Bacterial protease inhibitors constitute an interesting possibility, due to the fact that many specific and ubiquitous proteases have recently been characterised in some detail in both Gram-positive and Gram-negative pathogens. Unfortunately, at this moment few potent, specific inhibitors for such bacterial proteases have been reported, except for signal peptidase, clostripain, Clostridium histolyticum collagenase, botulinum neurotoxin and tetanus neurotoxin inhibitors (but such protease inhibitors are not used clinically for the moment). No inhibitors of the critically important and ubiquitous AAA proteases, degP or sortase have been reported, although such compounds would presumably constitute a new class of highly effective antibiotics. On the other hand, several bacterial proteases, such as the Clostridium histolyticum collagenase, or the botulinum neurotoxin A possess therapeutic applications per se for the treatment of some diseases or for the preparation of vaccines. This review presents the state of the art in the design of such enzyme inhibitors with potential therapeutic applications, as well as recent advances in the use of some of these proteases in therapy.