Antibiotics not at (total) fault for bacterial resistance

DURHAM, N.C.—Excessive use of antibiotics has long been lambasted as the main culprit at fault for growing bacterial resistance, but new research from a study led by Duke University researchers reveals that, with a few exceptions, antibiotics do not in fact promote the spread of bacterial antibiotic resistance through genetic swapping. Instead, these findings, which appeared in Nature Microbiology, imply that differential birth and death rates are responsible.

 

Bacteria are known to swap DNA via a process known as conjugation, which enables helpful genes to spread rapidly between individuals and species. As noted in a 1999 paper “Antibiotic resistance in microbes” in Cellular and Molecular Life Sciences: “Studies have shown that resistance determinants arise by either of two genetic mechanisms: mutation and acquisition. Antibiotic resistance genes can be disseminated among bacterial populations by several processes, but principally by conjugation. Thus the overall problem of antibiotic resistance is one of genetic ecology, and a better understanding of the contributing parameters is necessary to devise rational approaches to reduce the development and spread of antibiotic resistance.”

 

Due to the fact that the number of antibiotic-resistant bacteria rises when the drugs fail to kill them, the longstanding assumption has been that antibiotics increase the amount of genetic swapping that occurs. But the lead author of this study, Lingchong You, the Paul Ruffin Scarborough Associate Professor of Engineering at Duke University, postulated that instead it might be that the drugs wiped out the two “parent” strains, leaving a newly resistant strain of bacteria.

 

“The entire field knows there’s a huge problem of overusing antibiotics,” You said in a press release. “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.”

 

Allison Lopatkin, a doctoral student in You’s laboratory and lead author of the study, remarked that their work “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.”

 

To demonstrate this, Lopatkin placed bacterial cells in a kind of suspended animation where they could not reproduce or die, but where gene swapping could still occur, thereby removing the variable of birth and death rates and isolating bacterial response to antibiotics. Nine clinical pathogens commonly associated with the rapid spread of antibiotic resistance were tested and exposed to 10 common drugs that represented each major class of antibiotics.

 

What they found was that the rate of conjugation in each test remained flat and, in a few instances, even decreased slightly as the concentration of antibiotics grew. As noted in the study's abstract,

“Our modeling and experimental results demonstrate that conjugation dynamics are dictated by antibiotic-mediated selection, which can both promote and suppress conjugation dynamics. Our findings suggest that the contribution of antibiotics to the promotion of horizontal gene transfer may have been overestimated. These findings have implications for designing effective antibiotic treatment protocols and for assessing the risks of antibiotic use.”

 

“It would seem that when antibiotics are applied, the DNA swapping has already occurred and continues to do so,” You explained. “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.”

 

“This has direct implications in terms of how we design doses and protocols,” You added. “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.”

 

This study, “Antibiotics as a selective driver for conjugation dynamics,” was published in Nature Microbiology on April 11. Additional authors include Shuqiang Huang, Jaydeep Srimani and Tatyana Sysoeva of the You lab; Robert Smith from Nova Southeastern University; Sharon Bewick from University of Maryland; and David Karig from the Johns Hopkins University Applied Physics Laboratory.