Abstract
Multidrug-resistant (MDR) pathogens, particularly the ESKAPE group (Enterococcus faecalis/faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp.), have become a public health threat worldwide. Development of new antimicrobial classes and the use of drugs in combination are potential strategies to treat MDR ESKAPE pathogen infections and promote optimal antimicrobial stewardship. Here, the in vitro antimicrobial activity of robenidine analog NCL195 alone or in combination with different concentrations of three outer membrane permeabilizers [ethylenediaminetetraacetic acid (EDTA), polymyxin B nonapeptide (PMBN), and polymyxin B (PMB)] was further evaluated against clinical isolates and reference strains of key Gram-negative bacteria. NCL195 alone was bactericidal against Neisseria meningitidis and Neisseria gonorrhoeae (MIC/MBC = 32 μg/mL) and demonstrated synergistic activity against P. aeruginosa, E. coli, K. pneumoniae, and Enterobacter spp. strains in the presence of subinhibitory concentrations of EDTA, PMBN, or PMB. The additive and/or synergistic effects of NCL195 in combination with EDTA, PMBN, or PMB are promising developments for a new chemical class scaffold to treat Gram-negative infections. Tokuyasu cryo ultramicrotomy was used to visualize the effect of NCL195 on bioluminescent S. aureus membrane morphology. Additionally, NCL195’s favorable pharmacokinetic and pharmacodynamic profile was further explored in in vivo safety studies in mice and preliminary efficacy studies against Gram-positive bacteria. Mice administered two doses of NCL195 (50 mg/kg) by the intraperitoneal (IP) route 4 h apart showed no adverse clinical effects and no observable histological effects in major organs. In bioluminescent Streptococcus pneumoniae and S. aureus murine sepsis challenge models, mice that received two 50 mg/kg doses of NCL195 4 or 6 h apart exhibited significantly reduced bacterial loads and longer survival times than untreated mice. However, further medicinal chemistry and pharmaceutical development to improve potency, solubility, and selectivity is required before efficacy testing in Gram-negative infection models.
Highlights
Multidrug-resistant (MDR) pathogens, in particular the ESKAPE pathogens (Enterococcus faecalis/faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp.), are becoming a public health threat in both hospitals and the community
The results show that NCL195 alone demonstrated antimicrobial activity against the Neisseria isolates and type strains tested at 32 μg/mL, but no activity was observed against the other Gram-negative bacteria tested at up to 256 μg/mL
The results indicate a synergistic interaction of NCL195 and EDTA for E. coli ATCC 25922, E. coli ATCC 11229, K. pneumoniae ATCC 13883, P. putida ATCC 17428, P. aeruginosa PAO1, and P. aeruginosa ATCC 27853
Summary
Multidrug-resistant (MDR) pathogens, in particular the ESKAPE pathogens (Enterococcus faecalis/faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp.), are becoming a public health threat in both hospitals and the community. While there is an increasing trend of multidrug resistance in both Gram-negative and Gram-positive bacteria, there has been a significant global decline of investment into new drug development (Livermore, 2012; Woolhouse and Farrar, 2014). There are only a limited number of registered alternatives for MDR Gram-negative ESKAPE pathogens and few truly novel classes of antimicrobial agents undergoing preclinical testing in the drug development pipeline (Lepore et al, 2019). Within the new classes of antimicrobial agents being developed, most have activity only against Gram-positive pathogens, mainly due to the presence of an outer membrane in Gram-negative bacteria that deters the penetration and retention of antibiotics (Pushpakom et al, 2019; Theuretzbacher et al, 2019)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
