Bacterial proteolytic complexes as therapeutic targets

Abstract

Proteases have been successfully targeted for the treatment of several diseases, including hypertension, type 2 diabetes, multiple myeloma, HIV and hepatitis C virus infections. Given the demonstrated pharmacological tractability of this enzyme family and the pressing need for novel drugs to combat antibiotic resistance, proteases have also attracted interest as antibacterial targets--particularly the widely conserved intracellular bacterial degradative proteases, which are often indispensable for normal bacterial growth or virulence. This Review summarizes the roles of the key prokaryotic degradative proteases, with a focus on the initial efforts and associated challenges in developing specific therapeutic modulators of these enzymes as novel classes of antibacterial drugs.

The Mycobacterium tuberculosis Clp Gene Regulator Is Required for in Vitro Reactivation from Hypoxia-induced Dormancy

“…It has been suggested that Clp proteolysis is essential for the survival of Mtb, though this system is currently understudied. Furthermore, the Clp proteolysis complex is increasingly being recognized as a key druggable target (38), especially in Gram-positive bacteria (39,40), including Mtb (41-43). There are key implications of Rv2745c and the ATP-dependent Clp proteolysis genes being induced during stress.…”

Bacterial proteases, untapped antimicrobial drug targets

“…For example, cymA exhibits hepatic clearance and a short half-life in mice, and ecumicin has limited solubility and poor intestinal absorption. 13,73 Recent total syntheses and fermentation optimization may aid in these developments. [76][77][78] Although drugs targeting ClpC1 are an intriguing possibility for anti-M. tuberculosis therapeutics, they generally do not have bactericidal activity against species other than actinobacteria.…”

“…In contrast, intracellular proteases are multimeric complexes with little substrate specificity but whose activity and substrate selection are tightly regulated. 13 To achieve this level of regulation, catalytic sites are hidden in barrel-like structures and gaining access requires substrate selection and unfolding. In this way, the protease is able to specifically target a wide range of substrates, including not only Figure 1 Protease catalytic mechanisms.…”

“…Extracellular proteases are generally monomeric with high substrate specificity for a single protein or family of proteins. 13 They are often synthesized as inactive zymogens, protecting the cell from unregulated activity before secretion. In contrast, intracellular proteases are multimeric complexes with little substrate specificity but whose activity and substrate selection are tightly regulated.…”

“…The structure, function and role in pathogenesis of each protease has been reviewed previously. 13,17 Several of these complexes have been investigated as potential antibacterial targets, including Lon, 18 ClpXP, 19 HtrA 20 and the proteasome. 21 Of these, ClpXP has been most extensively investigated and is the only complex for which natural product inhibitors have been found thus far.…”