In vitro Activity of Repurposed Nitroxoline Against Clinically Isolated Mycobacteria Including Multidrug-Resistant Mycobacterium tuberculosis

Abstract

Antimicrobial treatment options for mycobacterial infections are limited due to intrinsic resistance and the emergence of acquired resistance in Mycobacterium tuberculosis. Isolates resisting first- and second line drugs are raising concerns about untreatable infections and make the development of new therapeutic strategies more pressing. Nitroxoline is an old oral antimicrobial that is currently repurposed for the treatment of urinary tract infection (UTI). In this study, we report the in vitro activity of nitroxoline against 18 clinical isolates of M. tuberculosis complex (MTBC) (M. tuberculosis N = 16, M. bovis BCG N = 1, M. bovis sp. bovis N = 1). Since nitroxoline achieves high concentrations in the urinary tract, we included all MTBC-isolates from urinary samples sent to our laboratory between 2008 and 2021 (University Hospital of Cologne, Germany). Isolates from other sources (N = 7/18) were added for higher sample size and for inclusion of drug-resistant M. tuberculosis isolates (N = 4/18). Based on our clinical routine the fluorescence-based liquid media system BACTEC MGIT 960 was used for susceptibility testing of nitroxoline and mainstay antitubercular drugs. Nitroxoline yielded a MIC90 of 4 mg/L for MTBC. In all M. tuberculosis isolates nitroxoline MICs were at least two twofold dilutions below the current EUCAST susceptibility breakpoint of ≤16 mg/L (limited to E. coli and uncomplicated UTI). In vitro activity of nitroxoline can be considered excellent, even in multidrug-resistant isolates. Future studies with in vivo models should evaluate a potential role of nitroxoline in the treatment of tuberculosis in the era of drug resistance.

Multipotential use of an old drug, as a new solution for anticancer therapy and multidrug-resistant urinary tract infections

“…W ostatnich latach, w związku z rozprzestrzenianiem się zakażeń grzybiczych na świecie oraz zwiększającej się lekooporności przeprowadzono badania w kierunku działania przeciwgrzybicznego nitroksoliny [9,10,11]. W związku ze zwiększoną ilością zachorowań na gruźlicę oraz zwiększoną opornością prątków gruźliczych, wykorzystano strategię repurposing, dzięki której wykazano aktywność NTX wobec niektórych prątków (M. tuberculosis, M. bovis) [21,22,23,24].…”

“…W związku z powyższym opracowywane są nowe strategie terapeutyczne w walce z M. tuberculosis (MTB). Jedną ze strategii jest repurposing środków przeciwdrobnoustrojowych zatwierdzonych do terapii innych zakażeń [21,22,23]. W badaniach wykazano aktywność wobec niektórych szczepów prątków (M. bovis i M. tuberculosis) [24].…”

“…Najwyższe MIC wynoszące 8mg/ml wykazano dla izolatu M. bovis BCG. W przypadku lekoopornych lub wielolekoopornych izolatów MTB opornych na izoniazyd i streptomycynę, a niektóre również na ryfampicynę i pirazynamid również wykazano wrażliwość tych szczepów na nitroksolinę [21].…”

Uncovering nitroxoline activity spectrum, mode of action and resistance across Gram-negative bacteria

“…1a) and FDA-approved antibiotic, used for more than 50 years as treatment and prophylaxis of acute and recurrent UTIs in several European and Asian countries [2][3][4] . Because of its excellent safety profile 3,[5][6][7] and activity against different organisms, nitroxoline has been recently proposed to be repurposed as antituberculosis 8 , antifungal 9,10 , antiviral 11,12 , antiparasitic 13 and anticancer [14][15][16][17] agent. Nitroxoline has been shown to exert bacteriostatic activity against a broad range of Gramnegative and Gram-positive species 18,19 .…”

Repurposing of Nitroxoline as an Alternative Primary Amoebic Meningoencephalitis Treatment

“…The mode of action is based on ion chelation with subsequent effects on enzymatic pathways and charges of cellular compartments of fungal and bacterial cells [ 25 ]. Recently, the activity of Nitroxoline against some emerging pathogens such as multidrug-resistant bacteria, including carbapenemase producers (enterobacterales), Neisseria gonorrhoeae , enterococci, Escherichia coli , staphylococci, and even drug-resistant fungi and mycobacteria, was demonstrated [ 23 , 26 , 27 , 28 , 29 ]. It has also been shown to be viricidal, being effective against Japanese encephalitis virus [ 30 ].…”