Analysis of core protein clusters identifies candidate variable sites conferring metronidazole resistance in .

BACKGROUND

Metronidazole is one of the first-line drugs of choice in the standard triple therapy used to eradicate infection. Hence, the global emergence of metronidazole resistance in poses a major challenge to health professionals. Inactivation of RdxA is known to be a major mechanism of conferring metronidazole resistance in However, metronidazole resistance can also arise in strains expressing functional RdxA protein, suggesting that there are other mechanisms that may confer resistance to this drug.

METHODS

We performed whole-genome sequencing on 121 clinical strains, among which 73 were metronidazole-resistant. Sequence-alignment analysis of core protein clusters derived from clinical strains containing full-length RdxA was performed. Variable sites in each alignment were statistically compared between the resistant and susceptible groups to determine candidate genes along with their respective amino-acid changes that may account for the development of metronidazole resistance in

RESULTS

Resistance due to RdxA truncation was identified in 34% of metronidazole-resistant strains. Analysis of core protein clusters derived from the remaining 48 metronidazole-resistant strains and 48 metronidazole-susceptible identified four variable sites significantly associated with metronidazole resistance. These sites included R16H/C in RdxA, D85N in the inner-membrane protein RclC (HP0565), V265I in a biotin carboxylase protein (HP0370) and A51V/T in a putative threonylcarbamoyl-AMP synthase (HP0918).

CONCLUSIONS

Our approach identified new potential mechanisms for metronidazole resistance in that merit further investigation.