Synthesis, structural characterization, and antimicrobial activity of Zn(cloxyquin)2: towards harnessing zinc intoxication and immune response restoration to combat Staphylococcus aureus and Mycobacterium tuberculosis

Abstract

Zinc is both essential and potentially toxic to microorganisms including pathogenic bacteria. To harness the antimicrobial activity of Zn, use of a suitable Zn ionophore is necessary to facilitate its penetration of the bacterial cell membrane. On the other hand, 5-chloro-8-hydroxyquinoline, also known as cloxyquin, has known antibacterial, anti-fungal and anti-protozoal activity and can act as a Zn ionophore. When cloxyquin is repurposed as a chelating agent to form the Zn complex Zn(cloxyquin)₂, the antimicrobial activity is enhanced by approximately 1000 times owing to a dual mode of action (MOA) by this Zn complex as opposed to cloxyquin itself. Specifically, the measured minimum inhibitory concentration (MIC) values of Zn(cloxyquin)₂ against five strains of pathogenic bacteria, including Staphylococcus aureus (SA) bacteria including methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate Staphylococcus aureus (VISA) and Erdman strain of Mycobacterium tuberculosis (Erdman Mtb), range from 2.5 to 9.5 μM, making it one of the most potent Zn-based antimicrobial metallodrugs reported in the literature thus far. Furthermore, drug resistance development by SA bacteria toward Zn(cloxyquin)₂ is considerably delayed when compared with ciprofloxacin and cloxyquin, respectively.