ClpP Protease, a Promising Antimicrobial Target

Abstract

The caseinolytic protease proteolytic subunit (ClpP) is a serine protease playing an important role in proteostasis of eukaryotic organelles and prokaryotic cells. Alteration of ClpP function has been proved to affect the virulence and infectivity of a number of pathogens. Increased bacterial resistance to antibiotics has become a global problem and new classes of antibiotics with novel mechanisms of action are needed. In this regard, ClpP has emerged as an attractive and potentially viable option to tackle pathogen fitness without suffering cross-resistance to established antibiotic classes and, when not an essential target, without causing an evolutionary selection pressure. This opens a greater window of opportunity for the host immune system to clear the infection by itself or by co-administration with commonly prescribed antibiotics. A comprehensive overview of the function, regulation and structure of ClpP across the different organisms is given. Discussion about mechanism of action of this protease in bacterial pathogenesis and human diseases are outlined, focusing on the compounds developed in order to target the activation or inhibition of ClpP.

Imipridone Anticancer Compounds Ectopically Activate the ClpP Protease and Represent a New Scaffold for Antibiotic Development

“…Antibiotics currently used in the clinic comprise only a small number of chemically distinct scaffold classes, all of which are decades old and target a limited number of cellular processes (Brown and Wright 2016). Despite the potential of ADEPs as a new scaffold class with a novel mechanism of action, preclinical development of ADEPs as antibiotics has been hampered by synthetic tractability, chemical stability, and pharmacokinetic issues (Hinzen et al 2006;Famulla et al 2016;Li et al 2017;Moreno-Cinos et al 2019). The imipridones, which already have excellent pharmacodynamic and toxicological characteristics, offer an opportunity to revisit ClpP activators as antibacterials.…”

“…ADEPs inhibit the growth of Gram-positive pathogens by causing massive unregulated intracellular proteolysis (Brötz-Oesterhelt et al 2005), and when used in combination with other antibiotics can efficiently eradicate antibiotic-tolerant persister cells (Conlon et al 2013). Even though ADEPs and various synthetic analogs demonstrate the potential of ClpP as a drug target (Bhandari et al 2018;Wong and Houry 2019), the low solubility, chemical instability, and poor pharmacodynamics of ADEPs have hampered therapeutic development (Brötz-Oesterhelt et al 2005;Moreno-Cinos et al 2019).…”

An allosteric switch regulates Mycobacterium tuberculosis ClpP1P2 protease function as established by cryo-EM and methyl-TROSY NMR

“…The ClpP protease is a major component of one of the main protein degradation systems in many bacteria (11)(12)(13)(14). ClpP is essential for homeostasis, pathogenesis, and virulence in several bacteria (12,15,16) and is considered a novel drug target for antibiotics that disrupt enzyme function as their mechanism of action (17)(18)(19)(20)(21). For example, cyclic acyldepsipeptides (ADEPs) cause unregulated activity in most bacterial ClpPs leading to the proteolysis of proteins necessary for survival and have proven to be an effective bactericide against antibiotic-resistant and persistent subpopulations of Staphylococcus aureus (22)(23)(24)(25).…”

Armeniaspirols inhibit the AAA+ proteases ClpXP and ClpYQ leading to cell division arrest in Gram-positive bacteria

“…ClpXP has been identified as a promising target for drug development due to its significant role in regulating virulence in diverse pathogens [19][20][21][22]133,134 . Pioneering work has uncovered synthetic β-lactone-, phenyl ester-, and boronate-based inhibitors of ClpXP [135][136][137] .…”