Peptidomimetics as Potential Anti-Virulence Drugs Against Resistant Bacterial Pathogens

Abstract

The uncontrollable spread of superbugs calls for new approaches in dealing with microbial-antibiotic resistance. Accordingly, the anti-virulence approach has arisen as an attractive unconventional strategy to face multidrug-resistant pathogens. As an emergent strategy, there is an imperative demand for discovery, design, and development of anti-virulence drugs. In this regard, peptidomimetic compounds could be a valuable source of anti-virulence drugs, since these molecules circumvent several shortcomings of natural peptide-based drugs like proteolytic instability, immunogenicity, toxicity, and low bioavailability. Some emerging evidence points to the feasibility of peptidomimetics to impair pathogen virulence. Consequently, in this review, we shed some light on the potential of peptidomimetics as anti-virulence drugs to overcome antibiotic resistance. Specifically, we address the anti-virulence activity of peptidomimetics against pathogens’ secretion systems, biofilms, and quorum-sensing systems.

Role of Enzymatic Activity in the Biological Cost Associated with the Production of AmpC β-Lactamases in Pseudomonas aeruginosa

“…In any case, besides the acquired enzymes, studies analyzing the biological cost associated with resistance mediated by the hyperproduction of intrinsic β-lactamases are almost nonexistent, although it is a topic that could help unveil therapeutically exploitable antivirulence targets ( 1 , 2 , 6 , 7 , 21 ). Since the mutation-driven hyperproduction of β-lactamases is a very common resistance mechanism in certain Gram-negative bacteria such as some Enterobacteriaceae members or P. aeruginosa , among others ( 43 ), it is certainly to be expected that it entails no great handicaps for the bacterium, at least in most situations.…”

“…To minimize this threat, some interesting alternatives are being investigated; for instance, those intended to interfere with bacterial pathogenesis (called antivirulence therapies) in order to increase the probabilities of the clearance of infection by the immune system and, thus, of milder clinical consequences are encouraging but remain at an experimental stage ( 5 ). Different strategies in this regard, such as interference with quorum sensing, neutralization of the toxin interaction site, blockade of secretion systems, modulation of the host microbiome, and antiadherence, etc., have been addressed, yet finding targets providing pathogenic attenuation is the essential first step in the development of these kinds of therapies ( 6 ). Although some exceptions may exist, and particularities such as the appearance of compensatory mutations, for instance, make the topic very complex, it is generally accepted that resistance is often associated with a fitness cost that impairs virulence, and thus, a deep understanding of the balance between these bacterial features is envisaged as a promising path to identify antivirulence-related Achilles’ heels ( 1 , 2 , 7 ).…”

The Role of Pseudomonas aeruginosa DsbA-1 in Bacterial Pathogenesis: Current Research and Future Prospects

“…Along with metabolomic profiling of compounds can be done. It is clear from various studies that disulfide bonds are crucial for protein stability and that DsbA facilitating disulfide bonds could be a crucial target for future mimetics that may be targeted to the hydrophobic domain of its enzymatic region [48]. Alternatively, novel downstream targets that affect pathogenesis, even more, could be targeted for drug design or mimetics.…”

“…Multiple strategies are used to limit biofilm-based infections on implants [46,47]. Research on DsbA mimetics and other targets could yield new treatment modalities [46,48,49].…”

Advances in Transdermal Delivery of Antimicrobial Peptides for Wound Management: Biomaterial-Based Approaches and Future Perspectives

“…To address these challenges, researchers are exploring various strategies, such as using nanodelivery systems, improving the activity and biocompatibility of AMPs, and developing peptidomimetics that mimic natural peptides . Additionally, the use of plant AMPs and immune homeostasis peptides is also being explored …”