Sorting out the Superbugs: Potential of Sortase A Inhibitors among Other Antimicrobial Strategies to Tackle the Problem of Antibiotic Resistance

Abstract

Rapid spread of antibiotic resistance throughout the kingdom bacteria is inevitably bringing humanity towards the “post-antibiotic” era. The emergence of so-called “superbugs”—pathogen strains that develop resistance to multiple conventional antibiotics—is urging researchers around the globe to work on the development or perfecting of alternative means of tackling the pathogenic bacteria infections. Although various conceptually different approaches are being considered, each comes with its advantages and drawbacks. While drug-resistant pathogens are undoubtedly represented by both Gram(+) and Gram(−) bacteria, possible target spectrum across the proposed alternative approaches of tackling them is variable. Numerous anti-virulence strategies aimed at reducing the pathogenicity of target bacteria rather than eliminating them are being considered among such alternative approaches. Sortase A (SrtA) is a membrane-associated cysteine protease that catalyzes a cell wall sorting reaction by which surface proteins, including virulence factors, are anchored to the bacterial cell wall of Gram(+) bacteria. Although SrtA inhibition seems perspective among the Gram-positive pathogen-targeted antivirulence strategies, it still remains less popular than other alternatives. A decrease in virulence due to inactivation of SrtA activity has been extensively studied in Staphylococcus aureus, but it has also been demonstrated in other Gram(+) species. In this manuscript, results of past studies on the discovery of novel SrtA inhibitory compounds and evaluation of their potency were summarized and commented on. Here, we discussed the rationale behind the inhibition of SrtA, raised some concerns on the comparability of the results from different studies, and touched upon the possible resistance mechanisms as a response to implementation of such therapy in practice. The goal of this article is to encourage further studies of SrtA inhibitory compounds.

Targeting Bacterial Sortases in Search of Anti-virulence Therapies with Low Risk of Resistance Development

“…The identification and analysis of the bacterial mechanisms of pathogenicity emerged as a promising strategy for drug development. The virulence factors are used by pathogens to colonize, invade, and persist within a susceptible host, surviving its immune system [ 5 ]. Bacteria use virulence factors to disable the host immune system and to invade its tissues.…”

“…The center of attention for this paper is one of the most promising anti-virulence strategies targeting prominent Gram-positive pathogens: the inhibition of bacterial sortases (Srt) using small molecules [ 5 ]. Even if the majority of Gram-positive bacteria contain at least one Srt enzyme, this work was focused on pathogens with a high risk for human health and with a low range of therapeutic solutions available, like Staphylococcus aureus ( S. aureus ), Staphylococcus epidermidis ( S. epidermidis ), Streptococcus mutans ( S. mutans ), Streptococcus pneumoniae ( S. pneumoniae ), Streptococcus pyogenes ( S. pyogenes ), Bacillus anthracis ( B. anthracis ), or Listeria monocytogenes ( L. monocytogenes ), highlighting therapeutically promising Srt inhibitors.…”

Sterically Hindered Quaternary Phosphonium Salts (QPSs): Antimicrobial Activity and Hemolytic and Cytotoxic Properties

“…The widespread use of antibiotics for the treatment of various diseases of nonbacterial etiology and other forms of misuse have led to the appearance of bacterial pathogens that are resistant to many well-known antibiotics [ 1 , 2 , 3 , 4 ]. The exceptional evolution of ESKAPE pathogens ( Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter species) has led to the emergence of “superbugs”, which have gained an extraordinary level of resistance [ 5 , 6 ]. The application of antibiotics has also led to the destruction of the human biota, resulting in reduced immune system activity and facilitating infection [ 7 ].…”

Role of the Sortase A in the Release of Cell-Wall Proteinase PrtS in the Growth Medium of Streptococcus thermophilus 4F44

“…Six classes (A to F) are distinguished, the most well-known being class A with SrtA of Staphylococcus aureus (for recent review, see [16]. In pathogen bacteria, sortases are then responsible for the anchoring of surface proteins involved in biofilm formation and/or their pathogenicity, and strategies of the inhibition of their activity are currently being developed [17,18].…”