Selection and characterisation of Staphylococcus aureus mutants with reduced susceptibility to the investigational oxazolidinone MRX-I.
MRX-I is a new oxazolidinone antimicrobial under development. In this study, the potential for development of resistance to MRX-I in Staphylococcus aureus was investigated and key mutations were characterised. Determination of spontaneous resistance frequency and the mutant selection window (MSW) were performed with meticillin-susceptible S. aureus (MSSA) ATCC 29213, meticillin-resistant S. aureus (MRSA) ATCC 33591 and two clinical MRSA isolates SA 0016 and SA 0017. Selected resistant mutants were sequenced for 23S rRNA as well as genes encoding the ribosomal proteins L3, L4 and L22. Resistance frequencies for the aforementioned strains were <8.25×10(-12), <6.33×10(-12), <2.96×10(-13) and <4.52×10(-13), respectively, and the MSW of MRX-I was 2-4, 1-4, 1-2 and 1-4 mg/L, respectively. After 30 serial passages, MRX-I minimum inhibitory concentrations (MICs) increased up to 8- to 16-fold both against MSSA and MRSA, whilst linezolid MICs increased 128-fold against MSSA and 16- to 32-fold against MRSA. MRX-I resistance mutations were clustered mainly in 23S rRNA and L3 protein regions. The U2504A transversion in 23S rRNA dominated in MRX-I-resistant mutants. No mutations in L4 and L22 proteins were observed. MRX-I exhibits a low potential to develop resistance in S. aureus, with a reduced resistance propensity compared with linezolid.
Institute of Antibiotics, Huashan Hospital, Fudan University, 12 M. Wulumuqi Road, Shanghai 200040, China.
Yanqin
Y
Huang
MicuRx (Shanghai) Pharmaceuticals, Inc., Shanghai 201203, China.
Yunhua
Y
Xu
MicuRx (Shanghai) Pharmaceuticals, Inc., Shanghai 201203, China.
Shicong
S
Liu
MicuRx (Shanghai) Pharmaceuticals, Inc., Shanghai 201203, China.
Hailin
H
Wang
Institute of Antibiotics, Huashan Hospital, Fudan University, 12 M. Wulumuqi Road, Shanghai 200040, China.
Xiaogang
X
Xu
Institute of Antibiotics, Huashan Hospital, Fudan University, 12 M. Wulumuqi Road, Shanghai 200040, China.
Qinglan
Q
Guo
MicuRx (Shanghai) Pharmaceuticals, Inc., Shanghai 201203, China.
Baixue
B
Wu
MicuRx Pharmaceuticals, Inc., Hayward, CA 94545, USA.
Mikhail F
MF
Gordeev
MicuRx Pharmaceuticals, Inc., Hayward, CA 94545, USA.
Wen
W
Wang
MicuRx (Shanghai) Pharmaceuticals, Inc., Shanghai 201203, China; MicuRx Pharmaceuticals, Inc., Hayward, CA 94545, USA.
Zhengyu
Z
Yuan
Institute of Antibiotics, Huashan Hospital, Fudan University, 12 M. Wulumuqi Road, Shanghai 200040, China. Electronic address: mgwang@fudan.edu.cn.
Minggui
M
Wang
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D008826:Microbial Sensitivity Tests; D009154:Mutation; D059645:Mutation Rate; D023303:Oxazolidinones / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D012338:RNA, Ribosomal, 23S / Q000235:genetics; D012269:Ribosomal Proteins / Q000235:genetics; D012641:Selection, Genetic; D012692:Serial Passage; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification
D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D011728:Pyridones; D012338:RNA, Ribosomal, 23S; D012269:Ribosomal Proteins; C000590780:contezolid
23S rRNA; MRX-I; Oxazolidinone resistance; Protein L3; Staphylococcus aureus