Targeting bacterial pathogenesis by inhibiting virulence-associated Type III and Type IV secretion systems

Abstract

Infections caused by Gram-negative pathogens pose a major health burden. Both respiratory and gastrointestinal infections are commonly associated with these pathogens. With the increase in antimicrobial resistance (AMR) over the last decades, bacterial infections may soon become the threat they have been before the discovery of antibiotics. Many Gram-negative pathogens encode virulence-associated Type III and Type IV secretion systems, which they use to inject bacterial effector proteins across bacterial and host cell membranes into the host cell cytosol, where they subvert host cell functions in favor of bacterial replication and survival. These secretion systems are essential for the pathogens to cause disease, and secretion system mutants are commonly avirulent in infection models. Hence, these structures present attractive targets for anti-virulence therapies. Here, we review previously and recently identified inhibitors of virulence-associated bacterial secretions systems and discuss their potential as therapeutics.

Primary architecture and energy requirements of Type III and Type IV secretion systems

“…Based on the structural similarity between T3SS and T4SS, it should be possible to find inhibitors that target different pathogens simultaneously. As only pathogenic bacteria express these secretion systems, non-pathogenic bacteria would not be targeted ( Blasey et al., 2023 ). Salicylidene acylhydrazides (SAHs), for instance, are a group of chemical inhibitors active against the T3 and T4SSs of several pathogens ( Mühlen and Dersch, 2020 ).…”

“…Since in these secretion systems the OM ring consists of pore-forming proteins that belong to the family of secretins, it is likely that this protein is the target of those compounds ( Felise et al., 2008 ). A recent extensive review ( Blasey et al., 2023 ) covers in depth the effects of many different inhibitors in both, T3 and T4SSs. Thus, it is not the aim of this work to focus on such analysis.…”

Click Triazole as a Linker for Pretargeting Strategies: Synthesis, Docking Investigations, Fluorescence Diagnosis, and Antibacterial Action Studies

“…Bioorthogonal chemistry realizes the pretargeting approach [ 24 , 25 , 26 , 27 , 28 ]. B8I-2 was discovered by Smith Mark A. et al to be able to attach to VirB8’s surface groove close to the dimerization site and prevent the assembly of the T4SS system [ 29 , 30 , 31 , 32 , 33 ]. According to B8I-2, we designed and synthesized three compounds A1 , A2, and A3 targeting VirB8 and A1 , A2, and A3 “click” with the four fluorescent probes T1 , T2 , T3, and T4 .…”