Research demonstrates the potential antimicrobial activity of squindoles by disrupting bacterial ion homeostasis

Antimicrobial resistance (AMR), a major global health threat, contributed to 1.27 million deaths in 2019. The mortality associated with AMR is projected to escalate to 10 million by 2050. The World AMR Awareness Week (WAAW), observed annually from November 18th to 24th, serves as a global initiative to enhance awareness and comprehension of AMR while advocating for best practices among global health stakeholders. The primary objective is to mitigate the emergence and dissemination of drug-resistant infections.

A recent study published in the journal Chem highlighted ‘squindoles’ as a novel anion-binding motif with effective chloride transport capabilities, demonstrating potent and swift antimicrobial effects against Staphylococcus aureus (SA) and methicillin-resistant Staphylococcus aureus (MRSA). Squindoles disrupt bacterial ion homeostasis, impacting chloride concentrations and revealing a direct correlation between compound activity and salt concentration. According to the researchers, this innovative mechanism represents a significant advancement in supramolecular medicinal chemistry, introducing a new class of antimicrobials that shows promise as a tool against antimicrobial resistance (AMR).

The study provides an initial comprehensive understanding of the antimicrobial effects displayed by synthetic transmembrane anion transporters. This discovery establishes their viability as a novel strategy against AMR and suggests a mechanism intricately linked to the disruption of sodium chloride homeostasis, effectively circumventing resistance mechanisms in MRSA. The researchers conclude that the newly identified anion-binding squindoles utilize NH and CH interactions to form robust bonds with chloride. X-ray crystallography analysis verifies the intended structure, illustrating the trans geometry of the indoline relative to the cyclobutene ring. This configuration creates a central binding pocket similar to symmetric squaramides.

The ongoing threat of AMR necessitates continuous exploration of novel strategies to combat bacterial infections effectively. This research on squindoles, revealing their potential as effective tools for disrupting bacterial ion homeostasis and combatting Gram-positive bacterial infections, contributes to the innovative approaches in the fight against AMR.

Reference

Brennan LE, Kumawat LK, Piatek ME, Kinross AJ, McNaughton DA, Marchetti L, et al. Potent antimicrobial effect induced by disruption of chloride homeostasis. Chem. 2023 Nov;9(11):3138–58.

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