Drug tolerance and resistance are major issues in healthcare today. New research suggests that the risk of these is greater in microbial communities featuring cooperating cells.
Antibiotic Resistance. Credit: Dr. Graham Beards
To make their findings, scientists analyzed data of more than 12,000 microbial communities from across the globe. These communities contain microorganisms that are both producing and absorbing chemical compounds needed for sustenance and growth.
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Drug tolerance exists when parasites, fungi, bacteria, and viruses show a reduced response to antimicrobial drugs. Resistance, on the other hand, occurs when microbes no longer respond to previously destructive treatments.
As an example of the risk, researchers say around 1.6 million people die each year as a result of invasive fungal infections. These result in more deaths globally than from malaria, as per study co-first author Jason Yu.
“There are currently only three classes of antifungal drugs in clinical use and in an increasing number of cases, these antifungals fail,” he said.
The research, which appeared in Nature Microbiology, could aid in making more effective treatments. It was carried out by scientists from the United Kingdom and Germany.
A paradox
The data that the scientists in this study used was obtained from the Earth Microbiome Project. In total, the team analyzed 12,538 microbial communities.
Researchers found that a specific cell type – auxotrophs – was very common. It was found in practically all communities analyzed (99.95 percent).
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Scientists deem the high prevalence of auxotrophs a paradox. Their presence would ordinarily be expected to hurt the communities that they are present in. This is because these cells do not make amino acids, vitamins, or other vital metabolites. They instead seem to deplete available resources.
“The widespread nature of auxotrophs has been considered a paradox, a fundamental problem in our understanding of microbiology,” stated co-first author Clara Correia-Melo. “This is because they must absorb metabolites from the environment and so they have been thought of as weaker than other cells which can create these chemical compounds themselves.”
She noted that auxotrophs are commonly considered “scrounger cells,” which drain communal resources.
How drug tolerance develops
Analyses of antimicrobial drug exposure showed that auxotrophs make communities more likely to develop tolerance against numerous drugs, compared to those without them. The cells were found to not just be scroungers but cooperators. While absorbing metabolites, they also give back other metabolites to their communities.
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Yeast model experiments shed light on how drug tolerance increases. Researchers observed that cooperation in metabolism results in increased metabolic export. As metabolites are moved out of cells, antimicrobial drugs are also expelled at an increased rate.
“This work solves a paradox around auxotroph success by revealing how auxotrophs are very valuable to their communities,” explained Correia-Melo, a molecular biology of metabolism researcher at the Francis Crick Institute. “They increase the metabolic interactions within the communities, and by so doing, increase the tolerance to drugs.”
She added that the increased metabolic flow also boosts the shared environment. More resources become available to cells in communities for growth and survival.
The researchers expressed hope that their findings would aid in developing new treatments that inhibit both cell growth and drug tolerance.
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