Abstract
Increasingly ineffective antibiotics and rapid spread of multi- and pan-resistant bacteria represent a global health threat; hence, the need of developing new antimicrobial medicines. A first step in this direction is identifying new molecular targets, such as virulence factors. Sortase A represents a virulence factor essential for the pathogenesis of Gram-positive pathogens, some of which have a high risk for human health. We present here an exhaustive collection of sortases inhibitors grouped by relevant chemical features: vinyl sulfones, 3-aryl acrylic acids and derivatives, flavonoids, naphtoquinones, anthraquinones, indoles, pyrrolomycins, isoquinoline derivatives, aryl β-aminoethyl ketones, pyrazolethiones, pyridazinones, benzisothiazolinones, 2-phenyl-benzoxazole and 2-phenyl-benzofuran derivatives, thiadiazoles, triazolothiadiazoles, 2-(2-phenylhydrazinylidene)alkanoic acids, and 1,2,4-thiadiazolidine-3,5-dione. This review focuses on highlighting their structure–activity relationships, using the half maximal inhibitory concentration (IC50), when available, as an indicator of each compound effect on a specific sortase. The information herein is useful for acquiring knowledge on diverse natural and synthetic sortases inhibitors scaffolds and for understanding the way their structural variations impact IC50. It will hopefully be the inspiration for designing novel effective and safe sortase inhibitors in order to create new anti-infective compounds and to help overcoming the current worldwide antibiotic shortage.
Highlights
The worldwide increasing resistance of bacterial pathogens to antibiotics imposes alternative strategies to treat infectious diseases [1,2]
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
A screening for S. aureus mutants that cannot cleave the protein A identified that bacteria defective in the anchoring of surface proteins is carrying a mutation in the srtA gene [9]
Summary
The worldwide increasing resistance of bacterial pathogens to antibiotics imposes alternative strategies to treat infectious diseases [1,2]. Bacteria use virulence factors to disable the host immune system and to invade its tissues. Drugs blocking these factors without killing the bacteria create less evolutionary pressure and diminish the chances of resistant genes to emerge. 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). 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
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