Dong Jinhui, Cheng Qian, Tang Chuanning, Zhong Yeteng, Wang Jieying, Lv Meiping, Chen Zhuolin, Li Peibo, Luo Ming, Pei Hua
Department of Clinical Laboratory, The Second Affiliated Hospital of Hainan Medical University, Haikou 571199, China.
Tuberculosis Research Units, Chongqing Public Health Medical Center, Chongqing 400036, China.
Pathogens. 2025 Feb 24;14(3):218. doi: 10.3390/pathogens14030218.
Oxazolidinones, novel synthetic antibacterials, inhibit protein biosynthesis and show potent activity against Gram-positive bacteria, including (MTB). In this study, we aimed to compare the in vitro activity of linezolid (LZD) and four oxazolidinones, including tedizolid (TZD), contezolid (CZD), sutezolid (SZD), and delpazolid (DZD), against multidrug-resistant tuberculosis (MDR-TB) and pre-extensively drug-resistant tuberculosis (pre-XDR-TB) isolates from Hainan. We established their epidemiological cut-off values (ECOFFs) using ECOFFinder software and analyzed mutations in (23S rRNA), , , , , , , , and genes to uncover potential mechanisms of oxazolidinone resistance. This study included 177 MTB isolates, comprising 67 MDR and 110 pre-XDR-TB isolates. Overall, SZD exhibited the strongest antibacterial activity against clinical MTB isolates, followed by TZD and LZD, with CZD and DZD showing equivalent but weaker activity (SZD = TZD < LZD < CZD = DZD; SZD < TZD = LZD < CZD = DZD). Significant differences in MIC distribution were observed for TZD ( < 0.0001), CZD ( < 0.01), SZD ( < 0.0001), and DZD ( < 0.0001) compared to LZD but not between MDR-TB and pre-XDR-TB isolates. We propose the following ECOFFs: SZD, 0.5 µg/mL; LZD, TZD, and CZD, 1.0 µg/mL; DZD, 2.0 µg/mL. No statistically significant differences in resistance rates were observed among these five drugs ( > 0.05). We found that eight MTB isolates (4.52% [8/177]) resisted these five oxazolidinones. Among these, only one isolate, M26, showed an amino acid substitution (Arg79His) in the protein encoded by the gene, which conferred cross-resistance to TZD and CZD. Three distinct mutations were identified in the gene; notably, isolate P604 displayed two insertions that contributed to resistance against all five oxazolidinones. However, no significant correlation was observed between mutations in the , , , , , , , , and genes with oxazolidinone resistance in the clinical MTB isolates tested. In summary, this study provides the first report on the resistance of MTB in Hainan to the five oxazolidinones (LZD, TZD, CZD, SZD, and DZD). In vitro susceptibility testing indicated that SZD exhibited the strongest antibacterial activity, followed by TZD and LZD, while CZD and DZD demonstrated comparable but weaker effectiveness. Mutations in and were discovered, but further research is needed to clarify their role in conferring oxazolidinone resistance in MTB.
恶唑烷酮类是新型合成抗菌药物，可抑制蛋白质生物合成，对包括结核分枝杆菌（MTB）在内的革兰氏阳性菌具有强效活性。在本研究中，我们旨在比较利奈唑胺（LZD）和四种恶唑烷酮类药物，即替加环素（TZD）、康替唑胺（CZD）、舒替利康（SZD）和地哌环素（DZD），对来自海南的耐多药结核病（MDR-TB）和广泛耐药结核病前体（pre-XDR-TB）分离株的体外活性。我们使用ECOFFinder软件确定了它们的流行病学临界值（ECOFFs），并分析了23S核糖体RNA、rpoB、rpoC、katG、inhA、embB、ahpC、fabG1和rpsL基因中的突变，以揭示恶唑烷酮类耐药的潜在机制。本研究包括177株MTB分离株，其中67株为MDR，110株为pre-XDR-TB分离株。总体而言，SZD对临床MTB分离株表现出最强的抗菌活性，其次是TZD和LZD，CZD和DZD表现出相当但较弱的活性（SZD = TZD < LZD < CZD = DZD；SZD < TZD = LZD < CZD = DZD）。与LZD相比，TZD（P < 0.0001）、CZD（P < 0.01）、SZD（P < 0.0001）和DZD（P < 0.0001）的MIC分布存在显著差异，但MDR-TB和pre-XDR-TB分离株之间没有差异。我们提出以下ECOFFs：SZD为0.5 µg/mL；LZD、TZD和CZD为1.0 µg/mL；DZD为2.0 µg/mL。这五种药物之间的耐药率没有统计学上的显著差异（P > 0.05）。我们发现8株MTB分离株（4.52% [8/177]）对这五种恶唑烷酮类药物耐药。其中，只有一株分离株M26在rpsL基因编码的蛋白质中出现了氨基酸取代（Arg79His），这赋予了对TZD和CZD的交叉耐药性。在rpoB基因中鉴定出三个不同的突变；值得注意的是，分离株P604显示出两个插入，这导致了对所有五种恶唑烷酮类药物的耐药性。然而，在所测试的临床MTB分离株中，rpoB、rpoC、katG、inhA、embB、ahpC、fabG1和rpsL基因中的突变与恶唑烷酮类耐药之间没有观察到显著相关性。总之，本研究首次报道了海南MTB对五种恶唑烷酮类药物（LZD、TZD、CZD、SZD和DZD）的耐药情况。体外药敏试验表明，SZD表现出最强的抗菌活性，其次是TZD和LZD，而CZD和DZD表现出相当但较弱的有效性。发现了rpoB和rpsL中的突变，但需要进一步研究以阐明它们在MTB对恶唑烷酮类药物耐药中的作用。
