Antivirulence therapy: type IV pilus as a druggable target for bacterial infections

Virulence is an organism's ability to infect the host and cause disease, and this ability is determined by the presence of virulence factors. The "do not kill, neutralize" strategy used by antivirulence therapies is a novel approach to managing the increasing drug resistance. In this respect, type IV pilus is one druggable target among many virulence factors. The type IV pili (T4P) assembly systems with adaptable and flexible filaments are utilized by numerous pathogens for infection. The current work focuses on druggable targets of T4aP with specific emphasis on Pseudomonas aeruginosa, Neisseria meningitidis, and Neisseria gonorrhoeae. Additionally, available information on potential inhibitor molecules that attenuate T4P activities or impair pilus function and/or assembly in different pathogens is summarized. The structural organization of T4aP suggests that ATPases, pilins, tip-associated adhesins, and peptidases could be considered potential target sites. As the number of high-resolution structures of different T4P systems and the computational power to model T4P machineries increase, the pace in the identification of novel molecules and targets to attenuate the activities of T4P will accelerate. Artificial intelligence, which has already penetrated into our daily lives, will definitely have a prominent role in providing a framework for progress in this area.