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

Proteases of the serine-, cysteine- and metallo- type are widely spread in many pathogenic bacteria, where they play critical functions related to col onisation 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 bios ynthesis, resistance to these pharmacological agents represents a serious m edical problem, which might be resolved by using a new generation of antibi otics with a different mechanism of action. Bacterial protease inhibitors c onstitute an interesting possibility, due to the fact that many specific an d ubiquitous proteases have recently been characterised in some detail in b oth Gram-positive and Gram-negative pathogens. Unfortunately, at this momen t few potent, specific inhibitors for such bacterial proteases have been re ported, except for signal peptidase, clostripain, Clostridium histolyticum collagenase, botulinum neurotoxin and tetanus neurotoxin inhibitors (but su ch protease inhibitors are not used clinically for the moment). No inhibito rs of the critically important and ubiquitous AAA proteases, degP or sortas e have been reported, although such compounds would presumable constitute a new class of highly effective antibiotics. On the other hand, several bact erial proteases, such as the Clostridium histolyticum collagenase, or the b otulinum neurotoxin A possess therapeutic applications per se for the treat ment of some disease or for the preparation of vaccines. This review presen ts the state of the art ina the design of such enzyme inhibits with potenti al therapeutic applications as well as recent advances in the use of some o f thee proteases in therapy.