Tobramycin-resistant small colony variant mutant of Salmonella enterica serovar Typhimurium shows collateral sensitivity to nitrofurantoin
Chang-Zhen Wang,
Yue-Jun Zhang,
Yue-Fei Chu,
Long-Gen Zhong,
Jin-Peng Xu,
Liu-Yan Liang,
Teng-Fei Long,
Liang-Xing Fang,
Jian Sun,
Xiao-Ping Liao,
Yu-Feng Zhou
Affiliations
Chang-Zhen Wang
Guangdong Laboratory for Lingnan Modern Agriculture, State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
Yue-Jun Zhang
Guangdong Laboratory for Lingnan Modern Agriculture, State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
Yue-Fei Chu
Guangdong Laboratory for Lingnan Modern Agriculture, State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
Long-Gen Zhong
Guangdong Laboratory for Lingnan Modern Agriculture, State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
Jin-Peng Xu
Guangdong Laboratory for Lingnan Modern Agriculture, State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
Liu-Yan Liang
Guangdong Laboratory for Lingnan Modern Agriculture, State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
Teng-Fei Long
Guangdong Laboratory for Lingnan Modern Agriculture, State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
Liang-Xing Fang
Guangdong Laboratory for Lingnan Modern Agriculture, State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
Jian Sun
Guangdong Laboratory for Lingnan Modern Agriculture, State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
Xiao-Ping Liao
Guangdong Laboratory for Lingnan Modern Agriculture, State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
Yu-Feng Zhou
Guangdong Laboratory for Lingnan Modern Agriculture, State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
ABSTRACTThe increasing antibiotic resistance poses a significant global health challenge, threatening our ability to combat infectious diseases. The phenomenon of collateral sensitivity, whereby resistance to one antibiotic is accompanied by increased sensitivity to another, offers potential avenues for novel therapeutic interventions against infections unresponsive to classical treatments. In this study, we elucidate the emergence of tobramycin (TOB)-resistant small colony variants (SCVs) due to mutations in the hemL gene, which render S. Typhimurium more susceptible to nitrofurantoin (NIT). Mechanistic studies demonstrate that the collateral sensitivity in TOB-resistant S. Typhimurium SCVs primarily stems from disruptions in haem biosynthesis. This leads to dysfunction in the electron transport chain (ETC) and redox imbalance, ultimately inducing lethal accumulation of reactive oxygen species (ROS). Additionally, the upregulation of nfsA/B expressions facilitates the conversion of NIT prodrug into its active form, promoting ROS-mediated bacterial killing and contributing to this collateral sensitivity pattern. Importantly, alternative NIT therapy demonstrates a significant reduction of bacterial load by more than 2.24-log10 cfu/g in the murine thigh infection and colitis models. Our findings corroborate the collateral sensitivity of S. Typhimurium to nitrofurans as a consequence of evolving resistance to aminoglycosides. This provides a promising approach for treating infections due to aminoglycoside-resistant strains.
