Antimicrobial polymers as therapeutics for treatment of multidrug-resistant Klebsiella pneumoniae lung infection

Abstract

Klebsiella pneumoniae (K. pneumoniae) is one of the most common pathogens in hospital-acquired infections. It is often resistant to multiple antibiotics (including carbapenems), and can cause severe pneumonia. In search of effective antimicrobials, we recently developed polyionenes that were demonstrated to be potent against a broad-spectrum of microbes in vitro. In this study, polyionenes containing rigid amide bonds were synthesized to treat multidrug-resistant (MDR) K. pneumoniae lung infection. The polyionene exhibited broad-spectrum activity against clinically-isolated MDR bacteria with low minimum inhibitory concentrations (MICs). It also demonstrated stronger antimicrobial activity against 20 clinical strains of K. pneumoniae and more rapid killing kinetics than imipenem and other commonly used antibiotics. Multiple treatments with imipenem and gentamycin led to drug resistance in K. pneumoniae, while repeated use of the polymer did not cause resistance development due to its membrane-disruption antimicrobial mechanism. Additionally, the polymer showed potent anti-biofilm activity. In a MDR K. pneumoniae lung infection mouse model, the polymer demonstrated lower effective dose than imipenem with negligible systemic toxicity. The polymer treatment significantly alleviated lung injury, markedly reduced K. pneumoniae counts in the blood and major organs, and decreased mortality. Given its potent in vivo antimicrobial activity, negligible toxicity and ability of mitigating resistance development, the polyionene may be used to treat MDR K. pneumoniae lung infection.

Statement of significance: Klebsiella pneumoniae (K. pneumoniae) is one of the most common pathogens in hospital-acquired infections, is often resistant to multiple antibiotics including carbapenems and can cause severe pneumonia. In this study, we report synthesis of antimicrobial polymers (polyionenes) and their use as antimicrobial agents for treatment of K. pneumoniae-caused pneumonia. The polymers have broad spectrum antibacterial activity against clinically isolated MDR bacteria, and eliminate MDR K. pneumoniae more effectively and rapidly than clinically used antibiotics. The polymer treatment also provides higher survival rate and faster bacterial removal from the major organs and the blood than the antibiotics. Repeated use of the polymer does not lead to resistance development. More importantly, at the therapeutic dose, the polymer treatment does not cause acute toxicity. Given its in vivo efficacy and negligible toxicity, the polymer is a promising candidate for the treatment of MDR K. pneumoniae-caused pneumonia.

Keywords: Antimicrobial polymer; Broad-spectrum antimicrobial activity; Klebsiella pneumoniae; Lung infection; Multidrug resistance; Polyionenes.