Non-gonococcal urethritis (NGU) is an infection of the urethra caused by pathogens other than gonococci that are transmitted through sexual contact. It is mainly caused by Chlamydia trachomatis (Ct) and Mycoplasma urealyticum (Uu) infections, with about 40% to 50% of cases caused by Chlamydia trachomatis and about 20% to 30% by Mycoplasma urealyticum. Due to the limitation of detection means, the clinical blind treatment has led to the increase of drug resistance year by year, and its drug resistance spectrum and degree of resistance may vary according to regional differences. In this paper, we review the progress of domestic and international research on drug resistance mechanisms of Mycoplasma and Chlamydia trachomatis. Mycoplasma is a class of prokaryotic microorganisms, the smallest microorganism that can reproduce in inanimate medium. There are two main types of mycoplasma that can cause genitourinary infections, namely Mycoplasma solium (Uu) and Mycoplasma humanum (Mh). In non-gonococcal urethritis, 20% to 40% of cases are caused by Mycoplasma urealyticum, and about 8% of cases are caused by Mycoplasma histolytica. Mycoplasma is naturally resistant to β-lactam antibiotics that interfere with cell wall formation, such as penicillin and cephalosporins, because it lacks a cell wall, and is sensitive to antibiotics that affect cellular protein synthesis, such as tetracyclines, quinolones, and macrolides, so these three classes of drugs are used clinically as the drugs of choice for NGU treatment, but resistant strains of these three classes of drugs have been isolated, making treatment However, drug-resistant strains of these drugs have been isolated, making treatment difficult. The study showed that Uu and Mh isolates were less effective against tetracyclines, and Uu had the highest resistance rate to tetracyclines with 32.1%, followed by macrolides and quinolones with 23.8% and 25.3%, and the smallest aminoglycosides with 7.9%. The overall resistance rate of Mh was significantly higher than that of UU, and the overall resistance trend was consistent, except for significant differences in the resistance to individual drugs. Blanchard et al. reported that the resistance of UU to tetracycline was determined by the tetM gene, but tetM was not resistant to doxycycline, suggesting that the resistance of UU to different drugs was controlled by different resistance genes and plasmids, and that the multiple resistance of multi-drug resistant UU strains to the same or different classes of antibiotics may be related to the presence of multiple resistance plasmids in multi-drug resistant UU strains. The tetM gene is the only gene known to mediate tetracycline resistance in Uu and Mh. The transacrylate obtained from the tetM gene can be integrated into mycoplasma chromosomal DNA, thereby causing mycoplasma to develop tetracycline resistance. DNA helicase and topoisomerase IV are the two target sites of fluoroquinolone action, which are encoded by two groups of genes, GyrA, GyrB and ParC, ParE, respectively. The mutation of these two groups of genes, resulting in the alteration of the target enzymes, will prevent the fluoroquinolones from entering the action zone, resulting in the development of drug resistance. As early as 1997, Bebear et al. conducted the first in vitro drug induction of Mh reference strain PG21, followed by GyrA and GyrB gene assays, and found that: after multi-step induction screening, four strains showed a C→T mutation at position 83 of the GyrA gene, resulting in a serine→leucine (Ser83→Leu) mutation, and showed high resistance to norfloxacin and ofloxacin. In addition to the common locus mutations in the GyrA gene, new mutation sites at position 95 of the GyrA gene have been identified recently. In 1998, Bebear et al. were the first to clone, sequence and systematically study the topoisomerase IV subunit ParC and ParE genes of the Mh reference strain PG21. The ParC gene is the original target site for the action of of ofloxacin, ciprofloxacin and nomefloxacin, as strongly suggested by the variation at loci 80 and 87 of the ParC gene. Recently, Bebear showed that in addition to the common GyrA gene 83 and 95 loci and ParC gene 80 and 87 loci mutations, the rare ParC gene 123 and 134 loci mutations were also found in Mh clinical isolates. Gushchin AE et al. found no genetic variation in some of the Mh in vitro-induced resistance strains, suggesting that other factors are involved in the resistance mechanism of Mh fluoroquinolones, such as the active drug exclusion system in the cell membrane. The resistance rate of macrolide antibiotics is high and should not be used as the first choice in clinical practice.Uu is more sensitive to the same macrolide class of cross-sampling and azithromycin, which may be related to the fact that the molecular chains of the chemical structure of these two antibiotics are different from other similar drugs, as well as the relatively few clinical applications in different regions. The resistance mechanism: erythromycin is an inducer of methylation enzymes, which causes methylation of the 50S subunit of the ribosome and leads to a change in the target of action, resulting in resistance to 14 and 15 ring macrolides, but remains sensitive to 16 ring drugs. Another study showed that mycoplasma resistance to macrolides was also associated with mutations in the 23S rRNA gene, leading to resistance to 16-membered macrolides. Mycoplasma pneumoniae and Mycoplasma humanum have been shown to be resistant to macrolides in association with mutations in the 23rRNA gene, but Mg has not been reported. Since the 1970s, Taylop-Robinson D and other scholars found that a curved microorganism could often be found in the urethral secretions of patients with non-gonococcal urethritis (NGU), and in 1981 Tully first isolated Mycoplasma genitalium (Mg) from this secretion using SP4 medium, which was the 13th mycoplasma isolated from humans. in 1988 some scholars used DNA probes to measure the presence of Mg in acute and chronic NGU, and this correlation was not associated with chlamydial infection. Fluoroquinolones have been effective in the treatment of Mg, but resistance has also occurred, and the mechanism may be related to mutations in the resistance-determining region, namely the gyrA and gyrB genes encoding type II Tsuge isomerase subunits A and B, and the genes encoding type IV Tsuge isomerase parC and parE. Mg and other mycoplasmas are generally insensitive to rifampicin. This is associated with a variation in the rpoB gene, which encodes the β subunit of the RNA polymorphase, the so-called “rif region”. The amino acid sequence encoded by the rpoB gene was determined and resistance was found to be associated with a change in histidine to asparagine at position 526. The mechanism of Chlamydia resistance Ct has not yet seen significant resistance to commonly used clinical antibiotics, after appropriate treatment, the occurrence of persistent infection is extremely rare. In France, tetracycline-resistant Ct strains have been reported to be able to form inclusion bodies when the concentration of tetracycline and doxycycline exceeds 64 mg/ml, while sensitive strains have MIC ≤ 0125 mg/ml for tetracycline and MBC ≤ 4 mg/ml. three strains of “heterotypic” resistant to various antibiotics have been isolated from treatment failure cases in the U.S. In the United States, three “heterotypic” strains of Chlamydia were isolated from treatment-naïve cases, which were resistant to tetracycline, erythromycin, sulfonamide, and clindamycin. In Israel, 44% of clinical strains were reported in 2001 to have varying degrees of decreased susceptibility to doxycycline or tetracycline. Ct infections in the male and female genital tract are often asymptomatic and tend to persist, when the typical chlamydial life cycle is interrupted and standard antibiotic treatment strategies do not always eradicate the infection.Somani et al. reported 2 cases of genital tract Ct infections that were ineffective with azithromycin, and drug sensitivity tests found that doxycycline, azithromycin, and ofloxacin at concentrations greater than 4.0ug/ml, respectively, failed to inhibit the growth of this clinical isolate. Bragina et al. observed 16 patients with persistent chlamydia after azithromycin treatment, and electron microscopy revealed morphological variation of chlamydia, with intracellular inclusion bodies either containing only reticulum or reticulum with abnormal outer membranes, and phagosomes with EB-containing extracellular monolayers or multilayers, which resembled the persistent state of chlamydia grown under unfavorable conditions, and this atypical morphological changes may reflect the persistence of Ct infection and relative resistance to antibiotics. Dessus-Babus et al. reported a case of a highly resistant L2 Ct strain with MIC values higher than 256ug/ml and 512ug/ml for ciprofloxacin and ofloxacin, respectively, showing complete cross-resistance. The clinical significance of the above laboratory results is unclear. The quinolone resistant strains could be obtained by repeated exposure of Ct to ofloxacin and sulforaphane, suggesting that in vivo resistance may occur during treatment of Ct infection with quinolones and that monitoring of this situation is necessary. decision region). Mutations in Ser83 within this region caused Ct resistance, suggesting that gyrA is the primary target site for the action of ofloxacin and sulforaphane. Other possible resistance mechanisms include decreased drug permeability and decreased active cellular uptake. Recently, there have been a few reports of tetracycline-resistant strains of Chlamydia trachomatis, but the resistant strains account for less than one percent of the total clinical isolates. two tetracycline-resistant strains of Chlamydia trachomatis, R19 and R27, were isolated by Lenart et al. and survived at 4ug/ml of tetracycline. However, the morphology of the inclusion bodies had changed by this time. Lefevre et al. isolated a tetracycline-resistant Chlamydia trachomatis strain from a patient with recurrent non-gonococcal urethritis. Their MIC and MBC for tetracycline were 64ug/ml, and for the other 34 non-resistant strains, the MIC was ≤0.25ug/ml. Giladi et al. found the presence of tetracycline-resistant genes in the DNA of Chlamydia, while Kaul found that the tetracycline-resistant genes were from Streptococcus and Campylobacter. In addition, Tam et al. found that chlamydial plasmid DNA contains anti-chloramphenicol resistance genes, which encode synthetic chloramphenicol acetyltransferases that degrade chloramphenicol. In conclusion, the antibiotic resistance properties of Chlamydia have not been established, but some resistant strains have been reported to cause treatment failure, so the problem of antibiotic resistance cannot be ignored. Laboratory studies have confirmed the existence of antibiotic resistance of Chlamydia trachomatis to quinolones, tetracyclines, and macrolides, and tetracycline resistance is the most prevalent and is consistent with clinical treatment ineffectiveness. Some of the mechanisms of quinolone resistance have been clarified, but it is unclear whether resistance causes ineffective treatment. Macrolide antibiotic resistance is relatively rare, and in the recent STD treatment guidelines issued by the Centers for Disease Control, the generally recommended regimens for Chlamydia trachomatis infection are azithromycin and doxycycline, with alternatives including erythromycin, erythromycin succinate &, ofloxacin, and trevafloxacin. Although in vitro drug sensitivity tests for many drugs have shown inhibition or killing properties of Chlamydia, it is difficult to treat ct infections with a highly potent drug. Moreover, the use of some antibiotics can cause a persistent state of Ct infection or cause drug resistance, resulting in poorer therapeutic outcomes. Therefore, there are still many problems in the treatment of Ct infection, such as the choice of treatment strategy, the resolution of drug resistance, the development of new antibiotics, etc., all need further research.