Virulence Factors of Pseudomonas Aeruginosa and Antivirulence Strategies to Combat Its Drug Resistance

Abstract

Pseudomonas aeruginosa is an opportunistic pathogen causing nosocomial infections in severely ill and immunocompromised patients. Ubiquitously disseminated in the environment, especially in hospitals, it has become a major threat to human health due to the constant emergence of drug-resistant strains. Multiple resistance mechanisms are exploited by P. aeruginosa, which usually result in chronic infections difficult to eradicate. Diverse virulence factors responsible for bacterial adhesion and colonization, host immune suppression, and immune escape, play important roles in the pathogenic process of P. aeruginosa. As such, antivirulence treatment that aims at reducing virulence while sparing the bacterium for its eventual elimination by the immune system, or combination therapies, has significant advantages over traditional antibiotic therapy, as the former imposes minimal selective pressure on P. aeruginosa, thus less likely to induce drug resistance. In this review, we will discuss the virulence factors of P. aeruginosa, their pathogenic roles, and recent advances in antivirulence drug discovery for the treatment of P. aeruginosa infections.

Keywords: Pseudomonas aeruginosa; antibiotic resistance; antivirulence strategies; infection; virulence factors.

Figure 1

The virulence factors of P. aeruginosa. The virulence factors of P. aeruginosa are divided into three main categories, namely bacterial surface structures, secreted factors, and bacterial cell-to-cell interaction. The bacterial surface structures include surface appendages like type IV pili and flagella, outer membrane components such as lipopolysaccharide, and five secretion systems (T1SS, T2SS, T3SS, T5SS, and T6SS). The secreted factors are illustrated in the black boxes. As for the bacterial cell-to-cell interaction, quorum sensing and biofilm are listed here.

Figure 2

Schematic illustration of the QS system in P. aeruginosa. There are four QS systems in P. aeruginosa, las, rhl, iqs and pqs. They included respectively the receptors LasR, RhlR, IqsR, and PqsR, the autoinducers OdDHL, C4HSL, IQS, and PQS, as well as the transcription factors LasI, RhlI, AmbBCDE, and PqsABCD. The arrows indicate a stimulatory effect, while the perpendicular line indicates an inhibitory effect. In the dashed box are the associated virulence factors and QS systems. HCN, hydrogen cyanide.

Figure 3

Schematic representation of tanshinones inhibiting T3SS needle elongation. PscF, PscG, and PscE form a complex that facilitates proper translocation of PscF and subsequent needle assembly (Quinaud et al., 2005; Feng et al., 2019). The tanshinones can act as competitive inhibitors to interrupt the complex formation, resulting in disruption of T3SS needle biogenesis (Quinaud et al., 2005; Feng et al., 2019).