Transcriptomic Responses to Polymyxin B and Analogues in Human Kidney Tubular Cells

Li, Mengyao1,2,4,5; Azad, Mohammad A. K.1,2; Thompson, Philip E.3; Roberts, Kade D.1,2; Velkov, Tony1,2; Zhu, Yan1,2,6; Li, Jian1,2

2023-02-01

10.3390/antibiotics12020415

Antibiotics-Basel   影响因子和分区

2079-6382

Polymyxins are last-line antibiotics for the treatment of Gram-negative 'superbugs'. However, nephrotoxicity can occur in up to 60% of patients administered intravenous polymyxins. The mechanisms underpinning nephrotoxicity remain unclear. To understand polymyxin-induced nephrotoxicity, human renal proximal tubule cells were treated for 24 h with 0.1 mM polymyxin B or two new analogues, FADDI-251 or FADDI-287. Transcriptomic analysis was performed, and differentially expressed genes (DEGs) were identified using ANOVA (FDR < 0.2). Cell viability following treatment with polymyxin B, FADDI-251 or FADDI-287 was 66.0 +/- 5.33%, 89.3 +/- 3.96% and 90.4 +/- 1.18%, respectively. Transcriptomics identified 430, 193 and 150 DEGs with polymyxin B, FADDI-251 and FADDI-287, respectively. Genes involved with metallothioneins and Toll-like receptor pathways were significantly perturbed by all polymyxins. Only polymyxin B induced perturbations in signal transduction, including FGFR2 and MAPK signaling. SIGNOR network analysis showed all treatments affected essential regulators in the immune system, autophagy, cell cycle, oxidative stress and apoptosis. All polymyxins caused significant perturbations of metal homeostasis and TLR signaling, while polymyxin B caused the most dramatic perturbations of the transcriptome. This study reveals the impact of polymyxin structure modifications on transcriptomic responses in human renal tubular cells and provides important information for designing safer new-generation polymyxins.

polymyxin nephrotoxicity transcriptomics metallothioneins

SCI

英语

其他

Australian National Health and Medical Research Council (NHMRC)[APP1104581]

Infectious Diseases ; Pharmacology & Pharmacy

Infectious Diseases ; Pharmacology & Pharmacy

WOS:000938149000001

MDPI

Web of Science

1.Monash Univ, Monash Biomed Discovery Inst, Infect Program, Melbourne, Vic 3800, Australia
2.Monash Univ, Dept Microbiol, Melbourne, Vic 3800, Australia
3.Monash Univ, Monash Inst Pharmaceut Sci, Med Chem, Parkville, Vic 3052, Australia
4.Southern Univ Sci & Technol, Clin Med Coll Jinan Univ 2, Shenzhen Peoples Hosp, Dept Crit Care Med,Affiliated Hosp 1, Shenzhen 518020, Peoples R China
5.Jinan Univ, Integrated Chinese & Western Med Postdoctoral Res, Guangzhou 510632, Peoples R China
6.Chinese Acad Sci, Tianjin Inst Ind Biotechnol, Tianjin 300308, Peoples R China

Li, Mengyao,Azad, Mohammad A. K.,Thompson, Philip E.,et al. Transcriptomic Responses to Polymyxin B and Analogues in Human Kidney Tubular Cells[J]. Antibiotics-Basel,2023,12(2).

Li, Mengyao.,Azad, Mohammad A. K..,Thompson, Philip E..,Roberts, Kade D..,Velkov, Tony.,...&Li, Jian.(2023).Transcriptomic Responses to Polymyxin B and Analogues in Human Kidney Tubular Cells.Antibiotics-Basel,12(2).

Li, Mengyao,et al."Transcriptomic Responses to Polymyxin B and Analogues in Human Kidney Tubular Cells".Antibiotics-Basel 12.2(2023).