Inhibiting the Evolution of Antibiotic Resistance

Abstract

Summary Efforts to battle anti-microbial resistance (AMR) are generally focused on developing novel antibiotics. However, history shows that resistance arises regardless of the nature or potency of new drugs. Here, we propose and provide evidence for an alternate strategy to resolve this problem: inhibiting evolution. We determined that the DNA translocase Mfd is an “evolvability factor” that promotes mutagenesis and is required for rapid resistance development to all antibiotics tested, across highly divergent bacterial species. Importantly, hypermutator alleles that accelerate AMR development did not arise without Mfd, at least during evolution of trimethoprim resistance. We also show that Mfd’s role in AMR development depends on its interactions with the RNA polymerase subunit RpoB and the nucleotide excision repair protein UvrA. Our findings suggest that AMR development can be inhibited through inactivation of evolvability factors (potentially with “anti-evolution” drugs), and in particular Mfd, providing an unexplored route towards battling the AMR crisis.

Putative TetR family transcriptional regulator Rv1019 ofMycobacterium tuberculosisis an auto-repressor and a negative regulator ofmfd-mazGoperon

“…Rv1019 , Rv1020 , Rv1021 gene locus is conserved in pathogenic mycobacteria such as M. tuberculosis , M. leprae , M. bovis and M. marinum as well as in non-pathogenic M. smegmatis . Mycobacterium is equipped with transcription-coupled repair (TCR), an effective method of detection and repair of DNA lesions caused by DNA damaging agents such as UV radiation and various oxidative stresses (29). UvrA, UvrB, UvrC, UvrD and Mfd of TCR system are essential for the repair of DNA lesions resulting from exposure to such DNA damaging environments (29–31).…”

“…Mycobacterium is equipped with transcription-coupled repair (TCR), an effective method of detection and repair of DNA lesions caused by DNA damaging agents such as UV radiation and various oxidative stresses (29). UvrA, UvrB, UvrC, UvrD and Mfd of TCR system are essential for the repair of DNA lesions resulting from exposure to such DNA damaging environments (29–31). Our results showed increased sensitivity of M. smegmatis expressing Rv1019 to UV light.…”

“…However, at this point we are unable to affirm whether this susceptibility is driven by the downregulation of Mfd or through an mfd -independent mechanism induced by Rv1019. A recent report suggests that Mfd could act as an ‘evolvability factor’ promoting antimicrobial resistance in Mtb (29). It will be interesting to know if Rv1019 plays the role of a key regulator of genetic changes in Mtb leading to drug resistance.…”

Mutators drive evolution of multi-resistance to antibiotics

“…Beyond increasing average mutation rates, increasing the variability has also been shown to increase the probability of multi-resistance (A lexander et al , 2017). Understanding the mechanistic underpinnings of mutation rates, and the relationship with resistance, will open the possibility for drugs that inhibit resistance evolution through suppressing mutations (R agheb et al , 2018).…”

Fighting the spread of antibiotic resistance with bacterial competence inhibitors

“…Such adjuvants can also go beyond the realm of common drugs to food compounds 28 . Other ideas involve searching for compounds that could reduce the evolution of resistance development, 29,30 or the use of quorum sensing analogous as modulators of pathogenic behaviours and players in biofilm formation 31 . Here, we propose the use of coadjuvants to prevent transformation and the associated spread of resistant genes and virulence factors by inhibiting pneumococcal competence.…”