AUTHOR=She Pengfei , Liu Yaqian , Xu Lanlan , Li Yimin , Li Zehao , Liu Shasha , Hussain Zubair , Wu Yong 

TITLE=SPR741, Double- or Triple-Combined With Erythromycin and Clarithromycin, Combats Drug-Resistant Klebsiella pneumoniae, Its Biofilms, and Persister Cells

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 12 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2022.858606

DOI=10.3389/fcimb.2022.858606

ISSN=2235-2988

ABSTRACT=Klebsiella pneumoniae has emerged as a major clinical and public health threat owing to the increasing prevalence of healthcare-associated infections caused by multidrug-resistant or extensively drug-resistant strains. However, increasing antibiotic resistance and the absence of clinically effective antimicrobial agents make combination therapy an urgent need. This study investigated the anti-microbial activity of SPR741, a polymyxin B derivative, in combination with macrolide antibiotics (erythromycin and clarithromycin), against K. pneumoniae and its extensively drug-resistant and pandrug-resistant clinical isolates. Monotherapy, double, and triple combination therapies were performed to identify the most effective treatment combination using in vitro checkerboard, time-killing kinetics. Furthermore, we evaluated the biofilm eradication and persister cell-killing activity of these combinations using laser confocal microscopy and colony forming unit counting. In addition, a neutropenic mouse thigh infection model was used to assess the therapeutic efficacy and toxicity of the triple antibiotic combination against pandrug-resistant K. pneumoniae in vivo. Our results suggested that SPR741 combined with macrolides exhibited strong synergistic bactericidal activity against extensively drug-resistant and pandrug-resistant K. pneumoniae. These antibiotic combinations could also effectively eradicate highly resistant biofilms and kill bacterial cells embedded in the biofilms of K. pneumoniae. SPR741-based double or triple combinations could also effectively kill K. pneumoniae persister cells in vitro and demonstrated considerable efficacy and low toxicity in a neutropenic mouse thigh infection model in vivo. In summary, our findings indicated that SPR741, in combination with macrolide antibiotics (double or triple combination), has the potential to serve as a novel treatment option against extensively drug-resistant and pandrug-resistant K. pneumoniae -related infections.