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

Abstract

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