Polymyxin B causes DNA damage in HK-2 cells and mice.
Arch Toxicol
; 92(7): 2259-2271, 2018 07.
Article
in En
| MEDLINE
| ID: mdl-29556720
ABSTRACT
Increasing incidence of multidrug-resistant bacteria presents an imminent risk to global health. Polymyxins are 'last-resort' antibiotics against Gram-negative 'superbugs'; however, nephrotoxicity remains a key impediment in their clinical use. Molecular mechanisms underlying this nephrotoxicity remain poorly defined. Here, we examined the pathways which led to polymyxin B induced cell death in vitro and in vivo. Human proximal tubular cells were treated with polymyxin B (12.5-100 µM) for up to 24 h and showed a significant increase in micronuclei frequency, as well as abnormal mitotic events (over 40% in treated cells, p < 0.05). Time-course studies were performed using a mouse nephrotoxicity model (cumulative 72 mg/kg). Kidneys were collected over 48 h and investigated for histopathology and DNA damage. Notable increases in γH2AX foci (indicative of double-stranded breaks) were observed in both cell culture (up to ~ 44% cells with 5+ foci at 24 h, p < 0.05) and mice treated with polymyxin B (up to ~ 25%, p < 0.05). Consistent with these results, in vitro assays showed high binding affinity of polymyxin B to DNA. Together, our results indicate that polymyxin B nephrotoxicity is associated with DNA damage, leading to chromosome missegregation and genome instability. This novel mechanistic information may lead to new strategies to overcome the nephrotoxicity of this important last-line class of antibiotics.
Key words
Full text:
1
Collection:
01-internacional
Health context:
2_ODS3
Database:
MEDLINE
Main subject:
Polymyxin B
/
DNA Damage
/
DNA Repair
/
Kidney
/
Anti-Bacterial Agents
Type of study:
Etiology_studies
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Arch Toxicol
Year:
2018
Document type:
Article