Bacterial protease inhibitors

Abstract

Serine-, cysteine-, and metalloproteases are widely spread in many pathogenic bacteria, where they play critical functions related to colonization and evasion of host immune defenses, acquisition of nutrients for growth and proliferation, facilitation of dissemination, or tissue damage during infection. Since all the antibiotics used clinically at the moment share a common mechanism of action, acting as inhibitors of the bacterial cell wall biosynthesis or affecting protein synthesis on ribosomes, resistance to these pharmacological agents represents a serious medical problem, which might be resolved by using new generation of antibiotics, possessing a different mechanism of action. Bacterial protease inhibitors constitute an interesting such possibility, due to the fact that many specific as well as ubiquitous proteases have recently been characterized in some detail in both gram-positive as well as gram-negative pathogens. Few potent, specific inhibitors for such bacterial proteases have been reported at this moment except for some signal peptidase, clostripain, Clostridium histolyticum collagenase, botulinum neurotoxin, and tetanus neurotoxin inhibitors. 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. 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.

Novel Inhibitors of the Pseudomonas aeruginosa Virulence Factor LasB: a Potential Therapeutic Approach for the Attenuation of Virulence Mechanisms in Pseudomonal Infection

“…Bacterial proteases play a pivotal role during infection (49,57), and the multifaceted role of LasB in pseudomonal virulence is no exception (28,38,49,58,60). LasB is a key factor in the biofilm pathway, in invasiveness, and in immunomodulation, each of which is instrumental in the establishment of a chronic pseudomonal infection.…”

Serine Protease PrtA from Streptococcus pneumoniae Plays a Role in the Killing of S. pneumoniae by Apolactoferrin

“…processing, the destruction of proteins involved in host immunity, and the activation of host proteases (45). The iron-binding proteins of the host, such as lactoferrin and transferrin, are major constituents of upper airway secretions and also play a significant role in modulation of the host immune response (21).…”

Inhibitors of bacterial N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE) and demonstration of in vitro antimicrobial activity

“…4,5 Thus, the search for new antibiotics that target enzymes in unexplored bacterial biosynthetic pathways is critically important, as confirmed in Supuran's excellent review of bacterial protease inhibitors. 6 The dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) enzyme is a member of the mesodiaminopimelate (mDAP)/lysine biosynthetic pathway. 7 The amino acids mDAP and/or lysine are essential components of the peptidoglycan cell wall for Gramnegative and most Gram-positive bacteria, providing a link between polysaccharide strands.…”