Quat disinfectants that swap nitrogen for phosphorus might stem antimicrobial resistance

Quaternary ammonium compounds, also known as quats or QACs, have for decades been a crucial weapon in the fight against bacteria and viruses. Approximately 47% of the disinfectants that the US Environmental Protection Agency lists as effective against the coronavirus that causes COVID-19 contain QACs, and demand for these chemicals has skyrocketed in recent years.

Increased use of QACs during the pandemic may have boosted antimicrobial resistance to both QACs themselves and antibiotics for treating infections. A new study, however, proposes an alternative suite of chemicals known as quaternary phosphonium compounds (QPCs), which feature a phosphorus atom where QACs’ nitrogen centers would be (ACS Infect. Dis. 2022, DOI: 10.1021/acsinfecdis.1c00611). The study suggests QPCs are more effective than commercial QACs against a broad spectrum of pathogens.

“QACs have been around for 85 years with a disappointing amount of innovation since,” says Kevin Minbiole, professor of chemistry at Villanova University and one of the study’s authors.

QPCs consist of cationic phosphonium heads and a hydrocarbon tail. The cationic heads are drawn towards the negative charge of a bacterial membrane, moving the tails into striking distance to pierce the membrane, thus disrupting the microbes’ integrity.

Minbiole and colleagues synthesized 59 different QPCs by varying the tail groups and the number of cationic heads on each molecule. The researchers then tested the chemicals with the best water solubility to see if they could kill six strains of bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli.

Overall, bisQPCs—QPCs with two phosphonium heads—were the most effective. One in particular, known as P6P-10,10, performed well against all six bacterial strains and was shown to be as much as 64 times more lethal against some of the strains compared with commercially available QACs. It’s thought that two cationic heads are better than one because they increase the QPC’s adhesion to the bacteria. But William Wuest, a chemist at Emory University who worked with Minbiole on the study, says the team still is not sure why two heads are better than three or four.

To check whether the bacteria could develop resistance to QPCs, the researchers administered low doses of the chemicals over a period of 30 days to see if the bacteria could figure out how to withstand QPC doses that were once lethal. They couldn’t, which pleasantly surprised the researchers. That’s not to say, however, that the bacteria won’t eventually evade QPCs, says Wuest.

“The compounds’ activity against single bacteria appears promising,” says Katharina Richter, a biomedical researcher at the University of Adelaide who wasn’t involved in the research. However, the study didn’t investigate biofilms, which are communities of bacteria that collaborate with each other and live within a slimy matrix of their own making. Because these structures are one of bacteria’s most resilient defenses against antimicrobials, they have “major implications on tolerance and resistance development, and so QPCs should also be investigated against biofilms.”