Sophie R. M. Mielke (Frankfurt a. M. / DE), Sarah Eckert (Frankfurt a. M. / DE), Denia Frank (Frankfurt a. M. / DE), Denise Bachmann (Frankfurt a. M. / DE), Eugen Proschak (Frankfurt a. M. / DE), Praveen Papareddy (Lund / SE), Heiko Herwald (Lund / SE), Kerstin Sander (London / GB), Thomas A. Wichelhaus (Frankfurt a. M. / DE)
Introduction:
Nitroxoline is an approved drug with highly potent, broad-spectrum antimicrobial activity against human pathogens, including multidrug-resistant strains. The clinical use, however, is limited to uncomplicated urinary tract infections due to insufficient organ distribution and cytotoxicity at higher doses. We aim to address these limitations by developing a nitroxoline conjugate with improved pharmacokinetic properties. Here, we present data on the in vitro antimicrobial activity of the NC. The project was funded by JPIAMR.
Materials & Methods:
The antimicrobial activity of NC was assessed against a broad panel of multidrug-resistant as well as susceptible clinical pathogens, e.g. Enterobacterales (n = 100), Pseudomonas aeruginosa (n = 20) and Acinetobacter baumannii (n = 20) as well as tuberculous and non-tuberculous mycobacteria (n = 48), enterococci (n = 30), staphylococci (n = 30) and Candida spp. (n = 35). The minimum inhibitory concentrations (MIC) of the NC were determined using the broth microdilution method. The building blocks of the conjugate were used as control substances. The mode of action, i.e. bactericidal or bacteriostatic, was determined by time-kill kinetics.
Results:
The MIC data obtained confirm the broad antimicrobial activity of nitroxoline against bacteria, including mycobacteria and yeasts. The NC showed good antimicrobial activity at an equimolar concentration, comparable to that observed with nitroxoline. For example, the NC MIC50 and MIC90 in mg/L were 0.5 and 1 for Staphylococcus aureus, 16 and 16 for Acinetobacter baumannii, 32 and 32 for Escherichia coli, 8 and 16 for mycobacteria, and 4 and 8 for Candida spp.. The mode of action was determined to be bactericidal and fungicidal for Staphylococcus aureus, Acinetobacter baumannii and Candida albicans, respectively.
Summary:
Our data show good antimicrobial activity of the nitroxoline conjugate in vitro and may indicate a promising approach in the fight against infections caused by multidrug-resistant pathogens. Further experiments are planned to investigate the toxicity and antimicrobial activity of NC in vivo.