The exponential rise of antibiotic drug resistance is a considerable threat to global public health. Researchers are continually searching for the underlying mechanisms that promote this resistant phenotype. Some evidence exists to suggest that antibiotic use encourages the spread of bacterial resistance through genetic swapping. However, new research suggests that these examples are outliers and not indicative of the majority of bacterial populations.

Researchers at Duke University suggest that differential birth and death rates of microbes and not DNA donation are to blame. The results have implications for designing antibiotic protocols to avoid the spread of antibacterial resistance.

This movie depicts how antibiotics can lead to increased populations of resistant bacteria through changes in death rates rather than an increase in the swapping of resistant genes. [Duke University]

“The entire field knows there’s a huge problem of overusing antibiotics,” noted senior study author Lingchong You, Ph.D., associate professor of engineering at Duke University. “It is incredibly tempting to assume that antibiotics are promoting the spread of resistance by increasing the rate at which bacteria share resistant genes with each other, but our research shows they often aren’t.”

Investigators have known for decades that bacteria can swap genetic elements through a process called conjugation, which allows helpful genes to spread quickly between individuals and even between species. Because the number of resistant bacteria rises when antibiotics fail to kill them, many researchers have assumed that the drugs increased the amount of genetic swapping taking place. The Duke researchers, however, hypothesized that the antibiotics were killing off the two “parent” lineages and allowing a newly resistant strain to thrive instead.

“Previous studies haven’t been able to tease these two ideas apart, but our work decoupled them,” explained lead study author Allison Lopatkin, a doctoral student in Dr. You’s laboratory. “We showed at the single-cell level that the exchange of resistant genes is not influenced by antibiotics at all, which is in contrast to the literature.”

In the study, the researchers put bacterial cells in a quasi-state of suspended animation, where they could neither die nor reproduce, but could still swap genes. With birth and death rates no longer a variable, the researchers could see how the frequency of gene exchange responded to antibiotics.

The Duke team tested nine clinical pathogens commonly associated with the rapid spread of resistance and exposed them to ten common drugs representing each major class of antibiotics. Interestingly, the rates of gene exchange in each test remained flat and, in a few cases, actually decreased slightly as the concentration of antibiotics grew.

The findings from this study were published recently in Nature Microbiology through an article entitled “Antibiotics As a Selective Driver for Conjugation Dynamics.”

“It would seem that when antibiotics are applied, the DNA swapping has already occurred and continues to do so,” Dr. You remarked. “Depending on their doses, the drugs can let the newly resistant bacteria emerge as the winners. When this occurs, the new strain is much more prevalent than before—if tests are run after some growth of the new strain.”

While there are a few proven examples of antibiotics directly inducing the expression of the genes responsible for donating resistance, they are very specific. For instance, the antibiotic tetracycline induces the expression of genes that only transfer tetracycline resistance.

This new study shows that despite these outliers, antibiotics do not promote resistance spread through the induction of global changes at the cellular level. The researchers are looking to further their research in the future, with the hope of helping clinicians design better antibacterial protocols.

“This has direct implications regarding how we design doses and protocols,” Dr. You stated. “Some antibacterial combinations can drastically promote the overall transfer dynamics. Other combinations, on the other hand, can suppress the pathogens equally well without promoting genetic transfers. These are the issues we’re hoping to address in follow-up research. We’re trying to learn how to design the antibiotic treatment protocols in such a way that they will be effective but won’t promote the spread of antibiotic resistance.”