The battle between medicine and harmful bacteria has traditionally centered on the hunt for new antimicrobial drugs, but the pathogens almost inevitably develop resistance to every type of antibiotic developed. A team at the University of Washington (UW), Seattle, has now developed a new strategy that thwarts this ability to develop antimicrobial drug resistance (AMR) by blocking the organisms’ capacity to mutate and evolve.

Mark N. Ragheb, lead author of the paper, in the UW Medicine lab.
Mark N. Ragheb, lead author of the paper, in the UW Medicine lab. [Houra Merrikh/UW Medicine]
The team, headed by Houra Merrikh, associate professor of microbiology at the UW medical school, found that a bacterial protein called Mfd acts as an “evolvability factor,” that plays a critical role in the ability of different types of pathogenic bacteria to mutate. Disabling the protein reduced mutation rate and the ability of pathogenic bacteria such as Mycobacterium tuberculosis (Mtb)and Salmonella typhimurium to develop resistance to antibiotics. Reporting on their studies in Molecular Cell, the researchers suggest that the development of  “anti-evolution drugs” that inactivate such evolvability factors represents an unexplored route towards “battling the AMR crisis.” Their published paper is titled “Inhibiting the evolution of antibiotic resistance.”

The fight between man and pathogens that have developed AMR is an “evolutionary arms race” that we are currently losing, the authors stated. Estimates suggest that antimicrobial resistance causes at least 700,000 deaths every year worldwide, a figure that could rise to 10 million by 2050 and surpass cancer as the primary global cause of death. Most of our strategies against pathogenic bacteria have focused on developing new antibiotic drugs, but, as the team noted, “resistance has arisen to every antibiotic used in the clinic.”

Many pathogenic bacteria, including the M. tuberculosis pathogen that causes tuberculosis, can rapidly mutate to generate strains that are resistant to antibiotics. In theory, reducing this mutational capacity by identifying and blocking factors that promote mutation could prevent such pathogens from developing AMR. The University of Washington team focused on the highly conserved bacterial DNA translocase protein Mfd, which—along with its functional analog in humans, CBS—is known to be involved in DNA repair mechanisms. Their new studies showed that Mfd also functions as a key evolvability factor that is critical to the ability of bacteria to mutate. The term evolvability factor refers to the ability of the protein to increase mutation rate and so accelerate bacterial evolution.

UW Med Antibiotics & Anti-Evolution Drug
Combining antibiotics with an anti-evolution drug that reduces the rate of mutations in the pathogen might be one strategy against the development of antimicrobial resistance. [Merrikh Lab/UW Medicine]
Tests in different types of pathogenic bacteria including S. typhimurium and M. tuberculosis showed that the protein promotes mutagenesis during growth in laboratory culture, and also during infection of eurkaryotic cells. The effects of Mfd-mediated mutagenesis was both conserved and seemed to be enhanced during bacterial growth and replication in the host. Lack of Mfd also prevented the bacteria from developing antimicrobial resistance. Tests using wild-type and Mfd-deficient M. tuberculosis showed marked differences in the ability to develop resistance to rifampicin, with the bacterial strains lacking Mfd demonstrating a 1,000-fold lower resistance to the drug. “These data suggest that, as observed in other species, Mfd is critical in the development of AMR in Mtb—a finding with potential clinical implications,” the authors stated.

Initial studies using S. typhimurium confirmed that Mfd promotes hypermutation—a key mechanism known to lead to rapid AMR development—and is critical to the development of AMR. Interestingly about half of the strains studied developed hypermutator alleles during the course of developing resistance to the drug trimethoprim. In contrast, strains lacking Mfd didn’t form hypermutator alleles.  “Generating hypermutation may offer an adaptive strategy to evolve high-level antibiotic resistance, and Mfd might promote this phenomenon,” the team wrote.

A suite of tests including evolutionary assays confirmed that Mfd supported the development of resistance to multiple types antibiotics by many different pathogenic bacteria tested. “… the data strongly suggest that Mfd promotes the evolution of resistance to antibiotics through its pro-mutagenic functions and that it may be critical for the acquisition of multiple mutations,” the authors stated.

What isn’t yet clear is how Mfd promotes mutagenesis and the development of antibiotic resistance, they acknowledge. One possible explanation is that the protein promotes mutagenic DNA repair through “error-prone” gap filling during the process of DNA repair. “Mfd may also promote DNA repair at sites that do not contain damaged DNA,” they added. It may also be possible that Mfd might promote mutagenesis by inhibiting other DNA repair pathways under normal growth conditions.

“Given our findings, we propose that blocking evolvability factors, and in particular Mfd, could be a revolutionary strategy to address the AMR crisis,” the authors stated. “A new class of “anti-evolution” drugs that target Mfd or other evolvability factors that promote mutagenesis may complement new antimicrobials and alleviate the problem of chromosomally acquired mutations that promote AMR … in principle, drugs that target Mfd (or key SOS factors) could be co-administered with antibiotics during treatment of infections, reducing the likelihood of resistance development at the onset of treatment.”

The authors said their studies also put an important message out to the drug discovery and development community, regarding the emphasis on targeting essential pathway proteins.  “… the effectiveness of this approach may be limited,” they noted. “Supplemental drugs that target non-essential proteins (e.g., Mfd) during the treatment of infections (or various diseases such as cancer) have the potential to significantly improve the efficiency and/or potency of current treatment regimens.”

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