If lone antibiotics cannot overcome resistant bacteria—a potentially life-threatening circumstance—multiple antibiotics may do better. Dual antibiotics, for example, can be deployed in combination. Another possibility, relatively overlooked, is to deploy two antibiotics in sequence, tag-team style. According to new research, the tag-team approach may work even better than ganging up, tornado-team style.

The new research indicates that drug treatments with two antibiotics can be designed to kill bacteria at dosages that would ordinarily cause rapid development of drug resistance and sustained bacterial growth, when administered alone or in combination. This result appeared April 8 in PLOS Biology, in an article entitled, “Using a Sequential Regimen to Eliminate Bacteria at Sublethal Antibiotic Dosages.”

The article is the result of an international collaboration led by Robert Beardmore, Ph.D., a professor of mathematical biosciences at the University of Exeter. Dr. Beardmore and colleagues used a test-tube model of a bacterial infection to show that, even in bacteria that already harbor drug resistance genes, sequential treatments could deal with the bacteria, even when much higher doses of single drugs or mixtures of two drugs failed to do so.

“Our study finds a complex relationship between dose, bacterial population densities and drug resistance,” explained Dr. Beardmore. “As we demonstrate, it is possible to reduce bacterial load to zero at dosages that are usually said to be sublethal and, therefore, are assumed to select for increased drug resistance.”

The PLOS Biology article highlights a phenomenon called collateral sensitivity. It can arise when measures taken by a bacterium to counter the presence of one antibiotic sensitize it to the subsequent use of another. To see if collateral sensitivity could be exploited, Dr. Beardmore’s team started by using mathematical predictions to validate an E. coli treatment model. This treatment model called for a sequential two-drug regimen: deploy the first drug, remove it, deploy the second drug, remove it, and then repeat the process.

The regimen was ultimately tested against an E. coli strain that had a multidrug pump encoded in its chromosomes that effluxed both antibiotics. Although genomic amplifications that increase the number of pumps expressed per cell can cause the failure of high-dose combination treatments, the sequential regimen, the researchers showed, could still eliminate resistant bacterial populations, even if sublethal doses were used.

“[We] investigated whether with two antibiotics and n rounds of treatment, if we search within the set of all possible 2n 'sequential treatments'—including the two single-drug monotherapies—there might be treatments within that set that are more effective than the equivalent two-drug cocktail,” wrote the authors of the PLOS Biology article. “Using a simple in vitro treatment model, we show that some sequential-in-time antibiotic treatments are successful under conditions that cause the failure of the cocktail treatment when implemented at the equivalent dosage.”

While bacteria are masters at adapting to antibiotic challenge, the new research suggests that there is a way to use this adaptation against them. The fluctuating environments created by well-designed sequential treatments can sensitize bacteria and render them susceptible to concentrations of antibiotics that would normally induce drug resistance and continued existence.

“Research has concentrated for decades on synergistic drug cocktails,” said study co-author Ayari Fuentes-Hernandez, Ph.D., an assistant professor of genomic sciences at the National Autonomous University of Mexico. “We believe 'sequential synergies' might be just as potent if we look for them, this research will therefore be of interest to the pharma and dwindling antibiotic discovery communities.”

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