Revisiting ESKAPE Pathogens: virulence, resistance, and combating strategies focusing on quorum sensing

Abstract

The human-bacterial association is long-known and well-established in terms of both augmentations of human health and attenuation. However, the growing incidents of nosocomial infections caused by the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter sp.) call for a much deeper understanding of these organisms. Adopting a holistic approach that includes the science of infection and the recent advancements in preventing and treating infections is imperative in designing novel intervention strategies against ESKAPE pathogens. In this regard, this review captures the ingenious strategies commissioned by these master players, which are teamed up against the defenses of the human team, that are equally, if not more, versatile and potent through an analogy. We have taken a basketball match as our analogy, dividing the human and bacterial species into two teams playing with the ball of health. Through this analogy, we make the concept of infectious biology more accessible.

Keywords: ESKAPE; antimicrobial resistance; biofilm; quorum sensing; virulence.

Figure 1

The ingenious game between team bacteria (ESKAPE) and team human. (A) The beginning: bacterial team facing the human team: bacterial team includes the Gram-positive Enterococcus sp., Staphylococcus aureus, and Enterobacter sp. and the Gram-negative Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa; the human team comprises macrophages, T-lymphocytes, B-lymphocytes, monocytes, eosinophils, and neutrophils. (B) Scores of the bacterial team: testament to their virulence factors. The bacterial players are rooted to the ground, closely adhering to the human body. The immune cells, however, cannot recognize them due to the masking effect of the bacterial capsule. To make things worse, another bacterium is spotted sharing its “special attribute” with their teammate. Ultimately, the bacterial team scores the goal, despite the efforts taken by the immune cell to block it. It is at this point that an antibiotic is spotted exclaiming its helplessness, being not recruited into the team. (C) Antibiotics: rise and fall. Although the antibiotics have achieved their goal, the bacteria have reduced their permeability, preventing the antibiotics from acting on them further. The bacterial players are also seen switching off the antibiotics by modifying them. Another bacterium is spotted in the act of slashing the functional antibiotic, rendering it inactive. Moreover, the antibiotic can no longer bind specifically to its target, as the bacterium has decoded the relentlessly used strategy of the human team and has modified the target. (D) The new substitutes are lined up: ready for action. The external coach, the researcher, is seen with a vaccine and monoclonal antibody on either side. Then comes the strong player representing various inhibitors—beta-lactamase inhibitor, efflux pump inhibitor, and conjugation inhibitor. Combinatorial drug molecules stand next to the highly versatile nanoparticles, winking and confirming their action plan. Next in the row is an immune booster. Adjacent to it, we see the grim-faced bacteriophage, which is waiting to take its toll! Lastly, we have the representative of antimicrobial light therapy holding a torch. (E) Alternate strategies: in action. The inhibitor is found to defend the antibiotic efficiently from the bacteria. Antimicrobial light therapy is affecting the bacteria. One bacterial player is alarmed at the entry of the combinatorial substitutes. Another bacterium is puzzled at the look of an immune cell drinking its energy potion! The monoclonal antibody has successfully recovered the ball of health from the bacterial team. Bacteriophage is doing its part by preventing bacterial players from entering human premises. (F) Quorum sensing and quorum-sensing inhibitors: decode and design. The bacterial players are spotted forming a protective shell (technically, biofilm) right below their goal post to defend their team. Among the four, two are caught communicating with each other, while the other pair is not, owing to the presence of a quorum-sensing inhibitor blocking their communication. On a closer look, the bacteria that cannot communicate with each other are equally unable to work with their injection (technically, express their virulence factor). This, in turn, has made them vulnerable to attack by the immune cell of the human team. Taking advantage of the current situation, the antibiotic has sneaked in and aims for the goal! Other players of the human team are seen guarding their goalpost against the entry of any bacterial player.

Figure 2

Comprehensive overview of the virulence factors of the ESKAPE pathogens. In the case of both Gram-positive bacteria (Enterococcus faecalis and Staphylococcus aureus) and Gram-negative bacteria (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter sp.), the host evasion is orchestrated by the recurring events: adhesion to the host cells, Degradation by a range of degradative enzymes and toxins establishes biofilm to trigger the innate immune pathways and further deteriorates the cellular homeostasis of the host cell. In addition, these bacteria also transfer their virulence factors through horizontal gene transfer, which leads to persistent infections. Created with BioRender.com.

Figure 3

Antibiotic resistance mechanism of ESKAPE pathogens. ESKAPE pathogens have developed various antibiotic resistance mechanisms against the different classes of antibiotics ranging from aminoglycosides to carbapenems. The exact ways each of these pathogens develops and disseminates resistance through biofilms vary widely. However, the most common mechanisms include the overexpression of efflux pumps, modification of cell wall composition and permeability, modification of the target, inactivation of the antibiotics, and reduction in antibiotic penetration through biofilm formation. Created with BioRender.com.

Figure 4

Quorum-sensing circuits of ESKAPE pathogens. All ESKAPE pathogens have been reported to have well-organized quorum-sensing circuits influencing their virulence and the ability to form biofilms. Four pathogens among the six, Enterococcus sp., Staphylococcus aureus, Klebsiella pneumoniae, and Enterobacter sp., involve LuxS system in altering antibiotic susceptibility and forming biofilms. More often than not, multiple quorum-sensing networks are involved in the biofilm formation process of these organisms. For instance, Pseudomonas aeruginosa is found to have a LasI–LasR system, RhII–RhIR system, and Quinolone and IQS systems in place to aid biofilm formation at various levels, including host tissue invasion and degradation. Similarly, the AbaI/AbaR system of Acinetobacter baumannii aids in its motility apart from contributing toward biofilm formation. Created with BioRender.com.