Antibiotic resistance of Klebsiella pneumoniae through β-arrestin recruitment-induced β-lactamase signaling pathway.

Overuse and misuse of antibiotics leads to rapid evolution of antibiotic-resistant bacteria and antibiotic resistance genes. Klebsiella pneumoniae has become the most common pathogenic bacterium accountable for nosocomial infections due to its high virulence factor and general occurrence of resistance to most antibiotics. The beta-lactamase signaling pathway has been suggested to be involved in antibiotic resistance against beta-lactams in Klebsiella pneumoniae. In the present study, the molecular mechanism of the antibiotic resistance of Klebsiella pneumoniae was investigated and the results indicated involvement of the beta-arrestin recruitment-induced beta-lactamase signaling pathway. Antimicrobial susceptibility of Klebsiella pneumoniae was assessed using automated systems and extended-spectrum beta-lactamase (ESBL) and beta-arrestin expression levels in Klebsiella pneumoniae were analyzed by reverse-transcription quantitative PCR. beta-lactam resistance in Klebsiella pneumoniae was determined using beta-lactam agar screening plates. The results demonstrated that beta-arrestin recruitment was increased in Klebsiella pneumoniae with antibiotic resistance (AR-K.P.) compared with that in the native Klebsiella pneumoniae strain (NB-K. P.). Increased production of ESBL was observed in AR-K. P. after treatment with the beta-lactam penicillin. Of note, inhibition of beta-arrestin recruitment significantly suppressed ESBL expression in AR-K.P. and in addition, genes encoding beta-arrestin and ESBL were upregulated in Klebsiella pneumoniae. Restoration of endogenous beta-arrestin markedly increased antibiotic resistance of Klebsiella pneumoniae to beta-lactam. Knockdown of endogenous beta-arrestin downregulated antibiotic resistance genes and promoted the inhibitory effects of beta-lactam antibiotic treatment on Klebsiella pneumoniae growth. In conclusion, the present study identified that beta-arrestin recruitment was associated with growth and resistance to beta-lactams, which suggested that beta-arrestin regulating ESBL expression may be a potential target for addressing antibiotic resistance to beta-lactams in Klebsiella pneumoniae.