HtrA family proteases of bacterial pathogens: pros and cons for their therapeutic use

Abstract

Background: Because there is an urgent need to develop antibacterial therapies other than antibiotics, research has increasingly focused on the high-temperature-requirement protein A (HtrA) family proteases, which have both serine protease and chaperone activities.Objectives: The research progresses of the role of HtrA family proteases in the pathogenesis of bacterial infections are summarized, and the pros and cons of exploiting HtrA inhibitors in antibacterial drug development are proposed. Sources: A search of PubMed was performed to identify relevant studies. Content: HtrA is essential for bacteria to survive in harsh environments, based on the degradation and refolding of misfolded proteins. Moreover, HtrA family protease can lyse the epithelial cell barrier to promote invasion and can also act as or assist virulence factors to enhance pathogenicity. On the other hand, HtrA secreted by certain bacteria can also affect intra-and interspecies biofilm formation (the mechanism of its promotion or inhibition has not yet been proven). Overall, in view of the role of the HtrA family in promoting bacterial pathogenicity, effective HtrA inhibitors may be an exciting direction for drug development. Therefore, the research progress regarding HtrA inhibitors are summarized and the risks of their application are discussed. Implications: This review will be useful both for investigators involved in the HtrA field as well as those wishing to acquire a basic understanding of the role and potential implementations of HtrA. Ruo-Yi Xue,

Function, molecular mechanisms, and therapeutic potential of bacterial HtrA proteins: An evolving view

“…In a recent review, Xue et al . briefly summarized the importance of HtrA in bacteria and drug development [73] . We see the HtrA protease as an interesting drug target due to its size, vital biological functions, highly conserved sequence and structure, and the presence within the PDZ domain of a clearly identifiable and highly specific binding site.…”

“…Irreversible analogues of JO146 showed inhibitory activity and are considered potential anti-chlamydial drugs ( Fig. 7 A) [20] , [73] . Modifications to the N-cap of these inhibitors only slightly alter their antibacterial activities, suggesting routes to future optimization.…”

Intestinal Organoids: New Tools to Comprehend the Virulence of Bacterial Foodborne Pathogens

“…Thus, additionally to its protease activity, EspP may be a factor involved in EHEC diarrheic episodes [ 81 ]. Broader research should investigate the role of serine protease activity from other enteric infectious agents in organoid-pathogenic phenotypes [ 82 ].…”

Pneumococcal Extracellular Serine Proteases: Molecular Analysis and Impact on Colonization and Disease

“…High protein sequence identity (up to 100%) of the HtrA protein was detected in six different pneumococcal strains ( Table 1 ) such as D39, Hungary 19A, serotype 19F_EF3030 and R6, indicating that HtrA is highly conserved. Therefore, it could be a desirable drug target to prevent pneumococcal diseases ( Wessler et al., 2017 ; Xue et al., 2021 ). In pneumococci, HtrA is a surface-exposed serine protease, easily accessible for potential inhibitory substances or anti-infectives.…”