Date Published: March 1, 2019
Publisher: Public Library of Science
Author(s): Huirong Zhang, Sangeevan Vellappan, M. Matt Tang, Xiaofeng Bao, Huizhou Fan, Xi Yang.
Chlamydia is a common pathogen that can causes serious complications in the reproductive system and eyes. Lack of vaccine and other effective prophylactic measures coupled with the largely asymptomatic nature and unrare clinical treatment failure calls for development of new antichlamydials, particularly selective antichlamydials without adverse effects on humans and the beneficial microbiota. We previously reported that benzal-N-acylhydrazones (BAH) can inhibit chlamydiae without detectable adverse effects on host cells and beneficial lactobacilli that dominate the human vaginal microbiota among reproductive-age women. However, the antichlamydial mechanism of BAH is not known. Whereas 4 single nucleotide polymorphisms (i.e., SNP1-4) were identified in a rare Chlamydia variant with a low level of BAH resistance, termed MCR, previous studies failed to establish a causal effect of any particular SNP(s). In the present work, we performed recombination to segregate the four SNPs. Susceptibility tests indicate that the R51G GrgA allele is both necessary and sufficient for the low level of BAH resistance. Thus, the Chlamydia-specific transcription factor GrgA either is a direct target of BAH or regulates BAH susceptibility. We further confirm an extremely low rate of BAH resistance in Chlamydia. Our findings warrant exploration of GrgA as a therapeutic and prophylactic target for chlamydial infections.
Chlamydiae are important and widespread pathogens. Chlamydia trachomatis is a leading infectious cause of blindness in many underdeveloped countries . Globally, C. trachomatis is the leading sexually transmitted bacterial pathogen with an estimated prevalence of 4.2% among women aged 15–49 years . In the United States, there has been a steep and sustained increase in sexually transmitted C. trachomatis infection in the past five years; 1.7 million cases were diagnosed in 2017, which represents a 22% increase from 2013, and accounts for 60% of cases of infections reported to the Centers for Disease Control and Prevention . Genital C. trachomatis infection in women often leads to serious complications including infertility, pelvic inflammatory syndrome, abortion or premature birth and ectopic pregnancy .
BAH belong to a novel group of selective antichlamydials [25, 26]. The genome of the rare BAH-resistant C. muridarum variant MCR carries four SNPs . Through extensive genetic analyses and susceptibility tests reported here, we have unequivocally established that the S4(R51G GrgA) allele is both necessary and sufficient for a low level of BAH resistance.