Since antibiotics use is currently limited due to undesired side effects and the increasing antibiotic
resistance of various bacteria strains, there is a pressing need to develop new strategies and methods preventing
The virulent potency of bacteria relies on a number of different extracellularly secreted factors among which
proteases considered as promising, novel drug targets are of special interest. The first evidence that bacterial
cysteine, serine and metalloproteinases contributed to the progression of infection was found in the early 70’s.
This extracellular proteolytic system allows bacteria to penetrate into tissues, escape detection by the host’s immune
mechanisms and grow despite limited access to nutrition. A molecule able to selectively inhibit the activity
of bacterial proteases in the spread of infection may lead to designing novel therapeutics. Moreover, due to their
mechanism of action, bacterial protease inhibitors can be used to fight antibiotic-resistant strains.
Herein, we undertake a review of various bacterial proteases together with the design and development of their
inhibitors (excluding β-lactams) for the last ten years, and introduce the reader to a brief history of the subject.