Lowering mutation rates in harmful bacteria might be an as yet untried way to hinder the emergence of antimicrobial pathogens. One target for drug development might be a protein factor, DNA translocase Mfd, which enables bacteria to evolve rapidly by promoting mutations in many different bacterial species.
This action speeds antibiotic resistance, including multi-drug resistance. Working on drugs to block Mfd and similar factors could be a revolutionary strategy to address the worldwide crisis of treatment-resistant infectious diseases.
With many disease-causing bacteria ratcheting up their shields against current drugs, new tactics are vital to protect people from treatment-resistant infections. Lowering mutation rates in harmful bacteria might be an as yet untried way to hinder the emergence of antimicrobial-resistant pathogens. The study is published in Molecular Cell.
While most efforts against antimicrobial resistance concentrate on producing better antibiotics, the scientists note, "History shows that resistance arises regardless of the nature or potency of new drugs."
In the search for another approach to combating this public health threat, the team of microbiologists, genome scientists, pathobiologists and molecular and cellular biologists found evidence for a key promoter of mutations in many different bacteria. This protein factor, translocase DNA, seems to speed resistance in various species to antibiotic that was tested.
Mfd "evolvability factors"
The call bacterial proteins like Mfd "evolvability factors" because, by increasing mutation rates, they propel the evolution of bacteria. Unlike many multicellular organisms, bacteria evolve quickly. This allows their species to survive or escape suddenly changing conditions, scarcity of nutrients and hostile environments – including attempts to destroy them with antibiotics or immune responses.
In studying what is behind trimethoprim resistance, for example, the researchers saw that potent, alternative genes that accelerate antibiotic resistance failed to crop up when Mfd was absent. In certain wild type strains of bacteria with Mfd that were studied, those that gained these so-called hypermutator alleles had a mutation rate that was more than 1,000 times that of their ancestral strain.
The researchers noted, "Generating hypermutation may offer an adaptive strategy to evolve high-level antibiotic resistance, and Mfd might promote this phenomenon." In other aspects of their project, the scientists reported that Mfd depends on certain other proteins that work on the bacterium's genetic machinery in order to carry out its job in antibiotic resistance.
Role of Mdf's
Mdf's role also might be enhanced or even exaggerated during bacterial infections of living things, in comparison to what happens when these bugs live in lab dishes.Mdf's role also might possibly be enhanced or even exaggerated during bacterial infections of living things, in comparison to what happens when these bugs live in lab dishes.
Among the several pathogens studied, the researchers were particularly interested in the mycobacterium that causes tuberculosis. They discovered what they describe as a "striking" difference in resistance to a representative antibiotic – rifampicin – in strains with and without Mfd.
The finding that Mfd is critical to the development of antibiotic resistance in mycobacterium TB could have potential clinical implications, the researchers noted mycobacterium TB could have potential clinical implications, the researchers noted.
A new class of anti-evolution drugs that target Mfd or other evolvability factors that promote mutations may complement new antimicrobials and alleviate the problem of chromosomally acquired mutations that leads to antimicrobial resistance.
Beyond the importance of reducing antibiotic resistance, there could be even greater implications of understanding and intervening in the evolutionary capacity of cells, according to the researchers. These include restraining genetic changes in cancer cells, and limiting the diversity in the strains of a pathogen a person's immune system is trying to overcome.
Supplemental drugs, such as the proposed evolution inhibitors, could, the predictive, improve the efficiency and effectiveness of current treatments, and expand the arsenal of drugs available to combat antimicrobial-resistant infections, cancers, and other diseases.