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.

Keywords: T3SS; T4SS; anti-virulence; bacterial pathogenesis; pathoblocker.

Figure 1

Schematic overview of the structure of type III and type IV secretion systems and potential inhibitor targets. (A) T3SSs consist of ring-shaped structures which form the basal body, spanning the inner (IM) and outer membrane (OM) of the bacterium. Cytoplasmic components, including the ATPase complex power needle assembly as well as the translocation of effector proteins. The needle ends in the needle tip, and the translocon forms a pore within the host cell membrane (HCM) through which unfolded effector proteins are translocated into the host cell. T3SSs target sites include secretion system assembly, needle or needle tip formation, translocon pore formation, ATPase function or effector protein secretion/translocation. (B) T4SSs consists of ring-like structures in the outer and inner membranes, which are connected through the stalk. At the inner membrane complex, an ATPase complex is located, providing energy for assembly and protein translocation. The pilus connects to the host cell membrane through which unfolded effector proteins are secreted into the host cell. Targets in T4SSs are secretion system assembly, VirB8 dimerization, ATPase function and effector secretion. (C) Additionally, inhibition can target virulence regulators, interfering with virulence gene or secretion system transcription.