A study by scientists at the University of Portsmouth, and at Naresuan and Pibulsongkram Rajabhat Universities, found that the naturally occurring compound hydroquinine has antibacterial activity against several microorganisms. The researchers, reporting on their findings in Tropical Medicine and Infectious Disease, suggest that the antimicrobial properties of the compound make it a potential candidate for future clinical investigation.
Robert Baldock, PhD, at the University of Portsmouth School of Pharmacy and Biomedical Sciences, said: “Using bacterial killing experiments, we found that hydroquinine was able to kill several microorganisms including the common multidrug-resistant pathogen Pseudomonas aeruginosa. “Characteristically, we also discovered that one of the main mechanisms used by these bacteria to escape killing activity of the drug was upregulated with treatment—indicating a robust response from the bacteria … By studying this compound further, our hope is that it may in future offer another line of treatment in combating bacterial infections.”
Baldock and colleagues reported their findings in a paper titled, “Hydroquinine Possesses Antibacterial Activity, and at Half the MIC, Induces the Overexpression of RND-Type Efflux Pumps Using Multiplex Digital PCR in Pseudomonas aeruginosa.”
Microbial multidrug resistance (MDR) has become one of the greatest threats to public health globally, the authors noted. Drug-resistant bacteria occur in more than 2.8 million infections and are responsible for 35,000 deaths per year. Common antibiotic-resistant superbugs cause diseases including sepsis, urinary tract infections, and pneumonia. “Pseudomonas aeruginosa, a non-glucose fermentative Gram-negative bacterium, is one of the most common opportunistic MDR pathogens, causing both hospital-acquired and community-acquired infections, e.g., in patients with burn wounds, cystic fibrosis, skin infections, and pneumonia,” the team wrote.
Statistics show that bloodstream infections caused by P. aeruginosa are associated with mortality rates of between 30% and 50%, and in intensive care units, the mortality rate of hospital-acquired pneumonia caused by P. aeruginosa can be up to 70%.
Hydroquinine, an organic compound that is found in the bark of some trees, is closely related to quinine-derivative drugs, and is already known to be an effective agent against malaria in humans. “Hydroquinine or dihydroquinine is an organic compound found in natural alkaloids (cinchona alkaloids) and is closely related to quinine,” the team explained. And while hydroquinine has also been found in abundance in some natural extracts that possess antibacterial properties, the team continued … “there is little evidence demonstrating the antibacterial effect of hydroquinine.”
For their study, Baldock and colleagues used a broth microdilution method to investigate whether hydroquinine displayed activity against different bacterial strains. Their results showed that the compound could inhibit both Gram-positive and Gram-negative bacteria, including Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and P. aeruginosa, at minimum inhibitory concentration (MIC) values of between 650 µg/mL and 2500 µg/mL. The studies also showed that hydroquinine killed all of the strains tested at minimum bactericidal concentration (MBC) values of between 1250 µg/mL, and 5000 µg/mL. “ … the results of this study indicate that hydroquinine is likely to be a good candidate for development with better antibacterial activity than the quinine-derivative, quinine dihydrochloride (which has an MIC of 125 grams/mL),” they wrote.
The authors are recommending further investigation into the antimicrobial resistance properties and potential side effects of hydroquinine. “…the mode of action of hydroquinine as an antibacterial has yet to be uncovered and is of keen interest for future study. In addition, the side effects of hydroquinine should be investigated in future studies due to the limitations of our research.”
Jirapas Jongjitwimol, PhD, from the department of medical technology at Naresuan University added: “Our future research aims to uncover the molecular target of hydroquinine. This would help our understanding of how the compound works against pathogenic bacteria and how it could potentially be used in a clinical setting.”
Interestingly, the scientists reported, the bactericidal concentrations of hydroquinine against the P. aeruginosa strains tested were 2–4-fold higher than those against the other strains tested (5000 µg/mL versus 1250–2500 µg/mL, respectively). Further investigation showed that P. aeruginosa overexpressed certain genes associated with the RND-type efflux pumps MexCD-OprJ and MexXY, in response to sub-inhibitory hydroquinine concentrations. “Using mRT-dPCR and RT-qPCR, we identified that mRNA levels of mexD and mexY genes were overexpressed in response to just half the MIC of hydroquinine in P. aeruginosa,” they wrote. “As hypothesized, this may form part of a compensatory response in P. aeruginosa in which RND efflux pumps are upregulated to aid the removal of hydroquinine and promote survival.”
RND-type efflux pumps recognize and expel a wide range of antibiotics, resulting in resistance to one or more drugs in microorganisms, the investigators pointed out. “… efflux pumps serve as an important protective mechanism against cellular stresses, antibiotics, and potentially harmful environmental factors.”
In conclusion, the team wrote, “… we uncover the antimicrobial potential of hydroquinine as well as identify changes in gene expression that may contribute to bacterial resistance. Further work will be required to explore the efficacy and potential use of hydroquinine in the clinic.”