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This report describes employment of response surface methodology and Box-Behnken designs in developing a spectrophotometric procedure for estimating nitroxoline in a micellar matrix based on cetylpyridinium chloride using a binary dimethyl sulfoxide:water solvent. The intensity of the absorption band at 448 nm was used as the target function. Independent factors were the cetylpyridinium chloride concentration, the pH of the medium, and the dimethyl sulfoxide volume fraction. Amathematical model and pairwise response surfaces with predictive value were constructed. Use of a desirability function yielded the optimal matrix for determining nitroxoline contents: a cetylpyridinium chloride concentration of 4.1 × 10–3M pH 7.6 and a dimethyl sulfoxide volume fraction of 0.4. This composition gave a linear calibration relationship over the concentration range 0.070–2.550 mg/ml and could be used to assess nitroxoline contents in medicines. Employment of the response surface methodology for estimating nitroxoline in medicines allowed a sensitive and selective technique using a micellar medium based on cetylpyridinium chloride and a spectrophotometric method of analysis to be developed. [ABSTRACT FROM AUTHOR]

ABSTRACTNew Delhi metallo-β-lactamase-1 (NDM-1) has rapidly disseminated worldwide, leading to multidrug resistance and worse clinical prognosis. Designing and developing effective NDM-1 inhibitors is a critical and urgent challenge. In this study, we constructed a library of long-lasting nitroxoline derivatives and identified ASN-1733 as a promising dual-functional antibiotic. ASN-1733 can effectively compete for Ca2+ on the bacterial surface, causing the detachment of lipopolysaccharides (LPS), thereby compromising the outer membrane integrity and permeability and exhibiting broad-spectrum bactericidal activity. Moreover, ASN-1733 demonstrated wider therapeutic applications than nitroxoline in mouse sepsis, thigh and mild abdominal infections. Furthermore, ASN-1733 can effectively inhibit the hydrolytic capability of NDM-1 and exhibits synergistic killing effects in combination with meropenem against NDM-1 positive bacteria. Mechanistic studies using enzymatic experiments and computer simulations revealed that ASN-1733 can bind to key residues on Loop10 of NDM-1, hindering substrate entry into the enzyme's active site and achieving potent inhibitory activity (Ki = 0.22 µM), even in the presence of excessive Zn2+. These findings elucidate the antibacterial mechanism of nitroxoline and its derivatives, expand their potential application in the field of antibacterial agents and provide new insights into the development of novel NDM-1 inhibitors.

The persistence of high incidence and mortality rates associated with urologic cancers underscores the urgent need for effective and safe treatments. Conventional chemotherapy regimens are often limited by their high toxicity, the cancer’s drug resistance, and the challenge of managing independently evolving multifocal spread. In this context, a repurposing strategy is particularly enticing. It allows for the introduction of a drug with a known safety profile, thus significantly reducing the costs and time necessary to introduce a new treatment. Nitroxoline (NIT), a drug with a well-established pharmacokinetic profile known for over 50 years and utilised in treating uncomplicated urinary tract infections, has recently garnered attention for its potential oncologic applications. Given the pharmacokinetic properties of NIT, our focus was specifically on urologic cancers in which its excretion profile is most advantageous. We examined all available studies, demonstrating significant effectiveness of NIT in inhibiting angiogenesis, tissue invasion, metastasis formation, and counteracting multidrug resistance. The efficacy and mechanism of action of NIT were found to vary across different cell lines. The findings to date are promising, suggesting that NIT or its derivatives could play a role in oncology, although further research is necessary to fully understand its potential and applicability in cancer treatment.

A patient in California, USA, with rare and usually fatal Balamuthia mandrillaris granulomatous amebic encephalitis survived after receiving treatment with a regimen that included the repurposed drug nitroxoline. Nitroxoline, which is a quinolone typically used to treat urinary tract infections, was identified in a screen for drugs with amebicidal activity against Balamuthia.

Introduction Nitroxoline is an old antimicrobial agent with a broad spectrum of pharmacological applications and a unique mechanism of action. However, its use in the treatment and prevention of urinary tract infections (UTIs) has not been popular in the recent past. Recently, nitroxoline is gaining interest, due to frequent drug-resistance in uropathogens. Unfortunately, there are few modern clinical trials assessing this antibiotic. Also, older researchers often do not meet current scientific standards. This review seeks to provide a comprehensive overview of nitroxoline as a viable option in treating uncomplicated lower UTIs. Material and methods A comprehensive literature search regarding the use of nitroxoline in UTIs was conducted using Pubmed, Cochrane Library and Embase databases. A cross-reference search was also performed. Case reports, editorials and non-peer-reviewed literature were excluded from further analysis. As a result, 21 publications were included in this review. Results The available literature on nitroxoline’s mechanism of action, pharmacokinetics, minimum inhibitory concentrations, in vitro activity and resistance rates strongly suggests that nitroxoline is a potent broad-spectrum antimicrobial agent. Moreover, clinical efficacy of the drug was analyzed – 2 articles proved high eradication rates in women with uncomplicated lower UTIs and 1 reported unsuccessful treatment in geriatric patients with lower complicated and uncomplicated UTIs. Finally, the present data on adverse effects indicate that nitroxoline is well-tolerated. Conclusions Nitroxoline is an obscure, yet potentially effective and safe antimicrobial agent in uncomplicated lower UTIs. Unfortunately, it is available only in a few countries. Nonetheless, nitroxoline can be useful in urological practice. [ABSTRACT FROM AUTHOR]

The persistence of high incidence and mortality rates associated with urologic cancers underscores the urgent need for effective and safe treatments. Conventional chemotherapy regimens are often limited by their high toxicity, the cancer's drug resistance, and the challenge of managing independently evolving multifocal spread. In this context, a repurposing strategy is particularly enticing. It allows for the introduction of a drug with a known safety profile, thus significantly reducing the costs and time necessary to introduce a new treatment. Nitroxoline (NIT), a drug with a well-established pharmacokinetic profile known for over 50 years and utilised in treating uncomplicated urinary tract infections, has recently garnered attention for its potential oncologic applications. Given the pharmacokinetic properties of NIT, our focus was specifically on urologic cancers in which its excretion profile is most advantageous. We examined all available studies, demonstrating significant effectiveness of NIT in inhibiting angiogenesis, tissue invasion, metastasis formation, and counteracting multidrug resistance. The efficacy and mechanism of action of NIT were found to vary across different cell lines. The findings to date are promising, suggesting that NIT or its derivatives could play a role in oncology, although further research is necessary to fully understand its potential and applicability in cancer treatment. [ABSTRACT FROM AUTHOR]

A novel, isocratic, sensitive, stability‐indicating high‐performance liquid chromatography method was developed for the separation and quantification of related substances in nitroxoline (NTL). The chromatographic separation has been achieved on Inertsil ODS‐3 V, (250 × 4.6 mm, 5 μm) at 240 nm using ethylenediamine tetraacetic acid buffer and methanol in the ratio of 60:40 v/v as mobile phase. The performance of the method has been checked as per the International Conference on Harmonization guidelines for specificity, linearity, accuracy, precision, and robustness. Regression analysis showed a correlation coefficient value greater than 0.99 for NTL and its three impurities. The detection limit of impurities was in the range of 0.01% (0.05 μg/mL)–0.22% (1.1 μg/mL) indicating the sensitivity of the newly developed method. The accuracy of the method was established based on the recovery obtained between 94.7% and 104.1% for all the impurities. The percentage relative standard deviation obtained for the repeatability was less than 4.0% at the specification level for all impurities. Forced degradation was performed to establish the stability‐indicating nature of the method and to know about the degradation products, the quality of a drug substance changes with time under the influence of stress conditions. Thus, the proposed method was validated and found to be specific, sensitive, linear, accurate, precise, reproducible, and beneficial for routine usage. [ABSTRACT FROM AUTHOR]

ABSTRACT Nitroxoline (NTX) is an antibiotic approved for the treatment of uncomplicated urinary tract infections (UTIs) caused by Enterobacteriaceae like Escherichia coli, and it has been on the market for more than 50 years. Despite being in use longer than several other clinically relevant antibiotics, the resistance of clinical isolates against NTX has not evolved significantly. To better understand this observation, we performed a standardized in vitro evaluation of NTX in comparison to other UTI drugs with a focus on resistance development and especially their consequences. We have managed to generate low-level resistant mutants in E. coli and Klebsiella pneumoniae using a long-term exposure setup, and identified mutations in different efflux-related genes and in other pleiotropic regulators as well as the sensor histidine kinase envZ. Subsequently, mutants were characterized by metabolic and proteomic analyses confirming major effects of NTX resistance on both metabolism and differential protein expression of E. coli, which ultimately also translates into reduced in vitro motility and in vivo virulence of mutant strains as shown in a zebrafish larvae infection model. IMPORTANCE Antimicrobial resistance (AMR) poses a global threat and requires the exploration of underestimated treatment options. Nitroxoline, an effective broad-spectrum antibiotic, does not suffer from high resistance rates in the clinics but surprisingly, it is not heavily used yet. Our findings provide compelling evidence that Nitroxoline resistance renders bacteria unable to cause an infection in vivo, thereby reinvigorating the potential of Nitroxoline in combating AMR.

Acanthamoeba is a ubiquitous genus of amoebae that can act as opportunistic parasites in both humans and animals, causing a variety of ocular, nervous and dermal pathologies. Despite advances in Acanthamoeba therapy, the management of patients with Acanthamoeba infections remains a challenge for health services. Therefore, there is a need to search for new active substances against Acanthamoebae. In the present study, we evaluated the amoebicidal activity of nitroxoline against the trophozoite and cyst stages of six different strains of Acanthamoeba. The strain A. griffini showed the lowest IC50 value in the trophozoite stage (0.69 ± 0.01 µM), while the strain A. castellanii L-10 showed the lowest IC50 value in the cyst stage (0.11 ± 0.03 µM). In addition, nitroxoline induced in treated trophozoites of A. culbertsoni features compatibles with apoptosis and autophagy pathways, including chromatin condensation, mitochondrial malfunction, oxidative stress, changes in cell permeability and the formation of autophagic vacuoles. Furthermore, proteomic analysis of the effect of nitroxoline on trophozoites revealed that this antibiotic induced the overexpression and the downregulation of proteins involved in the apoptotic process and in metabolic and biosynthesis pathways. [ABSTRACT FROM AUTHOR]

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Among the pathogenic free-living amoebae (FLA), Naegleria fowleri is the etiological agent of a fatal disease known as primary amoebic meningoencephalitis (PAM). Once infection begins, the lesions generated in the central nervous system (CNS) result in the onset of symptoms leading to death in a short period of time. Currently, there is no standardized treatment against the infection, which, due to the high virulence of the parasite, results in a high case fatality rate (>97%). Therefore, it is essential to search for new therapeutic sources that can generate a rapid elimination of the parasite. In recent years, there have already been several successful examples of drug repurposing, such as Nitroxoline, for which, in addition to its known bioactive properties, anti-Balamuthia activity has recently been described. Following this approach, the anti-Naegleria activity of Nitroxoline was tested. Nitroxoline displayed low micromolar activity against two different strains of N. fowleri trophozoites (IC50 values of 1.63 ± 0.37 µM and 1.17 ± 0.21 µM) and against cyst stages (IC50 of 1.26 ± 0.42 μM). The potent anti-parasitic activity compared to the toxicity produced (selectivity index of 3.78 and 5.25, respectively) in murine macrophages and human cell lines (reported in previous studies), together with the induction of programmed cell death (PCD)-related events in N. fowleri make Nitroxoline a great candidate for an alternative PAM treatment. [ABSTRACT FROM AUTHOR]

A patient in California, USA, with rare and usually fatal Balamuthia mandrillaris granulomatous amebic encephalitis survived after receiving treatment with a regimen that included the repurposed drug nitroxoline. Nitroxoline, which is a quinolone typically used to treat urinary tract infections, was identified in a screen for drugs with amebicidal activity against Balamuthia.

8‐Hydroxyquinoline and its derivatives consist of a group of metal‐binding ligands capable of reaching complexes that present several biological activities. In the present study, we collate and discuss data regarding the antileukemia activities of 8‐hydroxyquinoline (8HQ) compounds to provide an overview of their mechanisms of actions, and a compilation of cytotoxicity data against diverse leukemia cell lines. The pharmacological activities of this class of agents are associated primarily with their ability to coordinate metals and interact with multiple biological targets. We found consistent evidence that 8HQ exerts promising proapoptotic features through its direct interaction with deoxyribonucleic acid (DNA) and inhibition of multiple targets, such as the proteasome, nuclear factor kappa B (NF‐κB), histone deacetylase (HDAC), bromodomain and extra terminal (BET) proteins and janus kinases (JAKs), in addition to inducing autophagy associated cell death. Thus, we provide substantial evidence for the repositioning potential of the 8HQ class for the treatment of leukemia, a hematological malignancy for which urgent advances in therapeutic approaches are needed to overcome conventional therapy limitations. [ABSTRACT FROM AUTHOR]

Acanthamoeba is a ubiquitous genus of amoebae that can act as opportunistic parasites in both humans and animals, causing a variety of ocular, nervous and dermal pathologies. Despite advances in Acanthamoeba therapy, the management of patients with Acanthamoeba infections remains a challenge for health services. Therefore, there is a need to search for new active substances against Acanthamoebae. In the present study, we evaluated the amoebicidal activity of nitroxoline against the trophozoite and cyst stages of six different strains of Acanthamoeba. The strain A. griffini showed the lowest IC50 value in the trophozoite stage (0.69 ± 0.01 µM), while the strain A. castellanii L-10 showed the lowest IC50 value in the cyst stage (0.11 ± 0.03 µM). In addition, nitroxoline induced in treated trophozoites of A. culbertsoni features compatibles with apoptosis and autophagy pathways, including chromatin condensation, mitochondrial malfunction, oxidative stress, changes in cell permeability and the formation of autophagic vacuoles. Furthermore, proteomic analysis of the effect of nitroxoline on trophozoites revealed that this antibiotic induced the overexpression and the downregulation of proteins involved in the apoptotic process and in metabolic and biosynthesis pathways.

Introduction Nitroxoline (NTX) is a well-known chemotherapeutic agent that has been used to treat urinary tract infections since the 1960s. Today, the incidence of multidrug-resistant (MDR) bacterial strains is on the rise worldwide. This has resulted in repurposing, whereby during the ongoing research on nitroxoline, the possibility of its wide use has been demonstrated, not only in treatment against resistant pathogens, but also potential broad anti-cancer applications. Aim of the study The purpose of our work was to review scientific articles and show the multi-potential - anti-pathogenic and anti-tumor use of nitroxoline. Methods and materials We reviewed the English-language literature in the PubMed database, using the key words: „Nitroxoline”, „Nitroxoline cancer”, „Nitroxoline antibacterial use” Results Analysis of studies has shown that nitroxoline, currently used in benign urinary tract infections, is also applicable in the treatment of urinary tract infections caused by multidrug-resistant bacteria (MRD). It is also active against drug-resistant fungi and mycobacteria. Repurposing has also demonstrated the anticancer effects of nitroxoline through inhibition proliferation, induction apoptosis of tumor cells and other mechanisms, making it likely that nitroxoline will be used in cancer treatment regimens in the future. Conclusion Nitroxoline has found widespread use in the treatment of urinary tract infections caused by multidrug-resistant bacteria (MRD) and by strains of resistant fungi, which in today's world are spreading and increasing their drug resistance. Repurposing has shown promising anticancer activity of nitroxoline in the treatment of urinary tract cancers and more. The data supporting the effects of nitroxoline seem promising, suggesting the rationale for future clinical trials to further our understanding of the exact mechanisms of action and use of nitroxoline in oncology treatment.

Balamuthia mandrillaris is a pathogenic free-living amoeba that causes a rare but almost always fatal infection of the central nervous system called granulomatous amoebic encephalitis (GAE). Two distinct forms of B. mandrillaris-a proliferative trophozoite form and a nonproliferative cyst form, which is highly resistant to harsh physical and chemical conditions-have been isolated from environmental samples worldwide and are both observed in infected tissue. Patients suffering from GAE are typically treated with aggressive and prolonged multidrug regimens that often include the antimicrobial agents miltefosine and pentamidine isethionate. However, survival rates remain low, and studies evaluating the susceptibility of B. mandrillaris to these compounds and other potential therapeutics are limited. To address the need for more-effective treatments, we screened 2,177 clinically approved compounds for in vitro activity against B. mandrillaris The quinoline antibiotic nitroxoline (8-hydroxy-5-nitroquinoline), which has safely been used in humans to treat urinary tract infections, was identified as a lead compound. We show that nitroxoline inhibits both trophozoites and cysts at low micromolar concentrations, which are within a pharmacologically relevant range. We compared the in vitro efficacy of nitroxoline to that of drugs currently used in the standard of care for GAE and found that nitroxoline is the most potent and selective inhibitor of B. mandrillaris tested. Furthermore, we demonstrate that nitroxoline prevents B. mandrillaris-mediated destruction of host cells in cultured fibroblast and primary brain explant models also at pharmacologically relevant concentrations. Taken together, our findings indicate that nitroxoline is a promising candidate for repurposing as a novel treatment of B. mandrillaris infections.IMPORTANCEBalamuthia mandrillaris is responsible for hundreds of reported cases of amoebic encephalitis, the majority of which have been fatal. Despite being an exceptionally deadly pathogen, B. mandrillaris is understudied, leaving many open questions regarding epidemiology, diagnosis, and treatment. Due to the lack of effective drugs to fight B. mandrillaris infections, mortality rates remain high even for patients receiving intensive care. This report addresses the need for new treatment options through a drug repurposing screen to identify novel B. mandrillaris inhibitors. The most promising candidate identified was the quinoline antibiotic nitroxoline, which has a long history of safe use in humans. We show that nitroxoline kills B. mandrillaris at pharmacologically relevant concentrations and exhibits greater potency and selectivity than drugs commonly used in the current standard of care. The findings that we present demonstrate the potential of nitroxoline to be an important new tool in the treatment of life-threatening B. mandrillaris infections.

ABSTRACT New Delhi metallo- β -lactamase-1 (NDM-1) has rapidly disseminated worldwide, leading to multidrug resistance and worse clinical prognosis. Designing and developing effective NDM-1 inhibitors is a critical and urgent challenge. In this study, we constructed a library of long-lasting nitroxoline derivatives and identified ASN-1733 as a promising dual-functional antibiotic. ASN-1733 can effectively compete for Ca 2+ on the bacterial surface, causing the detachment of lipopolysaccharides (LPS), thereby compromising the outer membrane integrity and permeability and exhibiting broad-spectrum bactericidal activity. Moreover, ASN-1733 demonstrated wider therapeutic applications than nitroxoline in mouse sepsis, thigh and mild abdominal infections. Furthermore, ASN-1733 can effectively inhibit the hydrolytic capability of NDM-1 and exhibits synergistic killing effects in combination with meropenem against NDM-1 positive bacteria. Mechanistic studies using enzymatic experiments and computer simulations revealed that ASN-1733 can bind to key residues on Loop10 of NDM-1, hindering substrate entry into the enzyme's active site and achieving potent inhibitory activity (K i  = 0.22 µM), even in the presence of excessive Zn 2+ . These findings elucidate the antibacterial mechanism of nitroxoline and its derivatives, expand their potential application in the field of antibacterial agents and provide new insights into the development of novel NDM-1 inhibitors.

Among the pathogenic free-living amoebae (FLA), Naegleria fowleri is the etiological agent of a fatal disease known as primary amoebic meningoencephalitis (PAM). Once infection begins, the lesions generated in the central nervous system (CNS) result in the onset of symptoms leading to death in a short period of time. Currently, there is no standardized treatment against the infection, which, due to the high virulence of the parasite, results in a high case fatality rate (>97%). Therefore, it is essential to search for new therapeutic sources that can generate a rapid elimination of the parasite. In recent years, there have already been several successful examples of drug repurposing, such as Nitroxoline, for which, in addition to its known bioactive properties, anti-Balamuthia activity has recently been described. Following this approach, the anti-Naegleria activity of Nitroxoline was tested. Nitroxoline displayed low micromolar activity against two different strains of N. fowleri trophozoites (IC50 values of 1.63 ± 0.37 µM and 1.17 ± 0.21 µM) and against cyst stages (IC50 of 1.26 ± 0.42 μM). The potent anti-parasitic activity compared to the toxicity produced (selectivity index of 3.78 and 5.25, respectively) in murine macrophages and human cell lines (reported in previous studies), together with the induction of programmed cell death (PCD)-related events in N. fowleri make Nitroxoline a great candidate for an alternative PAM treatment.

Clioquinol and nitroxoline, two drugs with numerous pharmacological properties fallen into disuse for many decades. The first was considered dangerous due to contraindications and the second mainly because was taken as ineffective, despite its known antibacterial activity. In the last decades, the advances in pharmaceutical chemistry, molecular biology, toxicology and genetics allowed to better understand the cellular action of these compounds, some toxicological issues and/or activity scopes. Thus, a new opportunity for these drugs to be considered as potential antimicrobial agents has arisen. This review contemplates the trajectory of clioquinol and nitroxoline from their emergence to the present day, emphasizing the new studies that indicate the possibility of reintroduction for specific cases. [ABSTRACT FROM AUTHOR]

In the era of escalating antimicrobial resistance, the need for antibacterial drugs with novel or improved modes of action (MOAs) is a health concern of utmost importance. Adding or improving the chelating abilities of existing drugs or finding new, nature-inspired chelating agents seems to be one of the major ways to ensure progress. This review article provides insight into the modes of action of antibacterial agents, class by class, through the perspective of chelation. We covered a wide scope of antibacterials, from a century-old quintessential chelating agent nitroxoline, currently unearthed due to its newly discovered anticancer and antibiofilm activities, over the commonly used antibacterial classes, to new cephalosporin cefiderocol and a potential future class of tetramates. We show the impressive spectrum of roles that chelation plays in antibacterial MOAs. This, by itself, demonstrates the importance of understanding the fundamental chemistry behind such complex processes. [ABSTRACT FROM AUTHOR]

Abstract Background Mycoplasmas primarily cause respiratory or urogenital tract infections impacting avian, bovine, canine, caprine, murine, and reptilian hosts. In animal husbandry, mycoplasmas cause reduced feed-conversion, decreased egg production, arthritis, hypogalactia or agalactia, increased condemnations, culling, and mortality in some cases. Antibiotics reduce transmission and mitigate clinical signs; however, concerning levels of antibiotic resistance in Mycoplasma gallisepticum and M. capricolum isolates exist. To address these issues, we evaluated the minimum inhibitory concentrations (MICs) of halogenated phenazine and quinoline compounds, an N-arylated NH125 analogue, and triclosan against six representative veterinary mycoplasmas via microbroth or agar dilution methods. Thereafter, we evaluated the minimum bactericidal concentration (MBC) of efficacious drugs. Results We identified several compounds with MICs ≤25 μM against M. pulmonis (n = 5), M. capricolum (n = 4), M. gallisepticum (n = 3), M. alligatoris (n = 3), M. agassizii (n = 2), and M. canis (n = 1). An N-arylated NH125 analogue, compound 21, served as the most efficacious, having a MIC ≤25 μM against all mycoplasmas tested, followed by two quinolines, nitroxoline (compound 12) and compound 20, which were effective against four and three mycoplasma type strains, respectively. Nitroxoline exhibited bactericidal activity among all susceptible mycoplasmas, and compound 21 exhibited bactericidal activity when the MBC was able to be determined. Conclusions These findings highlight a number of promising agents from novel drug classes with potential applications to treat veterinary mycoplasma infections and present the opportunity to evaluate preliminary pharmacokinetic indices using M. pulmonis in rodents as an animal model of human infection.

BackgroundNitroxoline is an FDA-approved antibiotic with potential antitumor activity. Here we evaluated whether nitroxoline has antiproliferative properties on glioma cell growth in vitro and in vivo using glioma cell lines and a genetically engineered PTEN/KRAS mouse glioma model.MethodsThe effect of nitroxoline treatment on U87 and/or U251 glioma cell proliferation, cell-cycle arrest, invasion, and ability to induce an apoptotic cascade was determined in vitro. Magnetic resonance imaging was used to measure glioma volumes in genetically engineered PTEN/KRAS mice prior to and after nitroxoline therapy. Induction of apoptosis by nitroxoline was evaluated at the end of treatment using terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick end labeling (TUNEL).ResultsNitroxoline inhibited the proliferation and invasion of glioblastoma cells in a time- and dose-dependent manner in vitro. Growth inhibition was associated with cell-cycle arrest in G1/G0 phase and induction of apoptosis via caspase 3 and cleaved poly(ADP-ribose) polymerase. In vivo, nitroxoline-treated mice had no increase in tumor volume after 14 days of treatment, whereas tumor volumes doubled in control mice. Histological examination revealed 15%-20% TUNEL-positive cells in nitroxoline-treated mice, compared with ∼5% in the control group.ConclusionNitroxoline induces apoptosis and inhibits glioma growth in vivo and in vitro. As an already FDA-approved treatment for urinary tract infections with a known safety profile, nitroxoline could move quickly into clinical trials pending confirmatory studies.

In the era of escalating antimicrobial resistance, the need for antibacterial drugs with novel or improved modes of action (MOAs) is a health concern of utmost importance. Adding or improving the chelating abilities of existing drugs or finding new, nature-inspired chelating agents seems to be one of the major ways to ensure progress. This review article provides insight into the modes of action of antibacterial agents, class by class, through the perspective of chelation. We covered a wide scope of antibacterials, from a century-old quintessential chelating agent nitroxoline, currently unearthed due to its newly discovered anticancer and antibiofilm activities, over the commonly used antibacterial classes, to new cephalosporin cefiderocol and a potential future class of tetramates. We show the impressive spectrum of roles that chelation plays in antibacterial MOAs. This, by itself, demonstrates the importance of understanding the fundamental chemistry behind such complex processes.

Background: Mycoplasmas primarily cause respiratory or urogenital tract infections impacting avian, bovine, canine, caprine, murine, and reptilian hosts. In animal husbandry, mycoplasmas cause reduced feed-conversion, decreased egg production, arthritis, hypogalactia or agalactia, increased condemnations, culling, and mortality in some cases. Antibiotics reduce transmission and mitigate clinical signs; however, concerning levels of antibiotic resistance in Mycoplasma gallisepticum and M. capricolum isolates exist. To address these issues, we evaluated the minimum inhibitory concentrations (MICs) of halogenated phenazine and quinoline compounds, an N-arylated NH125 analogue, and triclosan against six representative veterinary mycoplasmas via microbroth or agar dilution methods. Thereafter, we evaluated the minimum bactericidal concentration (MBC) of efficacious drugs. Results: We identified several compounds with MICs ≤25 μM against M. pulmonis (n = 5), M. capricolum (n = 4), M. gallisepticum (n = 3), M. alligatoris (n = 3), M. agassizii (n = 2), and M. canis (n = 1). An N-arylated NH125 analogue, compound 21, served as the most efficacious, having a MIC ≤25 μM against all mycoplasmas tested, followed by two quinolines, nitroxoline (compound 12) and compound 20, which were effective against four and three mycoplasma type strains, respectively. Nitroxoline exhibited bactericidal activity among all susceptible mycoplasmas, and compound 21 exhibited bactericidal activity when the MBC was able to be determined. Conclusions: These findings highlight a number of promising agents from novel drug classes with potential applications to treat veterinary mycoplasma infections and present the opportunity to evaluate preliminary pharmacokinetic indices using M. pulmonis in rodents as an animal model of human infection. [ABSTRACT FROM AUTHOR]

The cause of urinary tract infections (UTI) is mostly bacteria. UTI is most often the result of colonization of microorganisms by the ascending route, less often blood or lymphatic, it can coexist with other urinary tract diseases, making treatment difficult. Nitroxoline is a urinary chemotherapy effective against numerous bacteria and fungi. Is a drug that is characterized by a unique mechanism of pharmacodynamic action, which consists in chelation of divalent cations, which is associated with a decrease in the activity of bacterial enzymes, in particular RNA polymerase. It is a valuable alternative in the treatment of urinary tract infections for furazidine and fluoroquinolones. [ABSTRACT FROM AUTHOR]

Nitroxoline is an effective antibacterial agent that is industrially produced by chemical and pharmaceutical enterprises in Ukraine. Parameters of its toxicity are determined under conditions of acute and subchronic toxicological experiments on 3 kinds of laboratory animals, by administering the drug orally and by application onto the skin and mucous membranes. The duration of acute experiment was 14 days, subchronical - 24 days. It was found that median lethal dose (DL50) for white female rats is 980 (852:1127) mg/kg, of white male rats – 835 mg/kg, white male mice– 660 mg/kg, by this parameter the drug can be attributed to 3 class of hazard – moderately hazardous substance. Average effective time of death (ET50) for albino rats is 28 hours. Species sensitivity of laboratory animals to nitroxoline is slightly expressed. The death of the animals starts on the first day after the injection and is recorded during three days of the experiment. In application on intact skin, locally-irritant and skin-resorptive effects are absent. After contact with the mucous membrane of the eye the drug causes weak irritant effect. Nitroxoline has a moderate cumulative activity.

Nitroxoline is an effective antibacterial agent that is industrially produced by chemical and pharmaceutical enterprises in Ukraine. Parameters of its toxicity are determined under conditions of acute and subchronic toxicological experiments on 3 kinds of laboratory animals, by administering the drug orally and by application onto the skin and mucous membranes. The duration of acute experiment was 14 days, subchronical - 24 days. It was found that median lethal dose (DL50) for white female rats is 980 (852:1127) mg/kg, of white male rats – 835 mg/kg, white male mice– 660 mg/kg, by this parameter the drug can be attributed to 3 class of hazard – moderately hazardous substance. Average effective time of death (ET50) for albino rats is 28 hours. Species sensitivity of laboratory animals to nitroxoline is slightly expressed. The death of the animals starts on the first day after the injection and is recorded during three days of the experiment. In application on intact skin, locally-irritant and skin-resorptive effects are absent. After contact with the mucous membrane of the eye the drug causes weak irritant effect. Nitroxoline has a moderate cumulative activity.

Importance: Antimicrobial resistance (AMR) poses a global threat and requires the exploration of underestimated treatment options. Nitroxoline, an effective broad-spectrum antibiotic, does not suffer from high resistance rates in the clinics but surprisingly, it is not heavily used yet. Our findings provide compelling evidence that Nitroxoline resistance renders bacteria unable to cause an infection in vivo , thereby reinvigorating the potential of Nitroxoline in combating AMR., Competing Interests: The study was financed by MIP Pharma Holding (Germany), which manufacturer and distributes Nitroxoline. MIP Pharma was involved in planning of the study but had no influence on data collection, analysis, interpretation, or the content of this manuscript. The authors affirm that the potential conflicts of financial interest have not influenced the objectivity, integrity, or validity of the research findings presented herein. We disclose these conflicts to ensure transparency and maintain the highest standards of scientific integrity.

Urinary tract infections (UTI) are one of the most often infectious diseases in hospital and ambulatory practice. They are usually caused by Gram-negative rods, mainly Escherichia coli. In the context of increased acquired resistance of uropathogens to orally administered the first choice drugs (cotrimoxazole, nitrofurantoin, fosfomycin, trimetoprim) and the second choice drugs (fluoroquinochinolones), oral nitroxoline (5-nitro-8-hydroxyquinoline) has received renewed attention in the management of acute and recurrent UTI caused by E. coli in adults. In this paper mode of antibacterial action, pharmacokinetic and pharmacodynamic properties, activity against E. coli and other Gram-negative rods including multidrug resistance were presented. Considering the good safety and efficacy as also wide increase of resistance of uropathogens against cotrimoxazole and fluoroquinolones, nitroxoline should be reconsidered as one of the first line drug for the treatment of uncomplicated UTI. Varied sensitivity of other rods from Enterobacterales to nitroxoline needs more studies to widen alternatively indications for nitroxoline in UTI. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance has become a prime global concern. An ability of the microbes to produce enzymes to destroy antimicrobial drugs is one of the well-known mechanisms underlying the resistance. 8-Hydroxyquinoline (8HQ) and derivatives were reported to exert diverse biological effects such as antimicrobial, antioxidant and antineurodegenerative activities. Herein, 8HQ (1), nitroxoline (NQ, 2) and 7 -Br-8HQ (3) were investigated for antimicrobial activity against Enterobacteriaceae including extended spectrum β-lactamase (ESBL)-producing and carbapenemase-producing strains as well as the effect of metal ions .These compounds (1-3) displayed the great antimicrobial activity against fifty-eight bacterial isolates of Escherichia coli, Providencia rettgeri and Klebsiella pneumoniae, in which NQ (2) exerted the highest antimicrobial activity with a MIC50 of 42.04 μM (8 μg/mL) and MBC50 of 168.28 μM (32 μg/mL). The MIC values of NQ (2) and 7-Br -8HQ (3) were significantly increased in the presence of Cu2+ and Fe3+. This finding reveals that NQ could be an effective compound to be further developed as an antimicrobial agent for combating Enterobacteriaceae infections. [ABSTRACT FROM AUTHOR]

Lyme disease, caused by Borrelia burgdorferi, is the most common vector-borne disease in USA, and 10–20% of patients will develop persistent symptoms despite treatment (“post-treatment Lyme disease syndrome”). B. burgdorferi persisters, which are not killed by the current antibiotics for Lyme disease, are considered one possible cause. Disulfiram has shown to be active against B. burgdorferi, but its activity against persistent forms is not well characterized. We assessed disulfiram as single drug and in combinations against stationary-phase B. burgdorferi culture enriched with persisters. Disulfiram was not very effective in the drug exposure experiment (survival rate (SR) 46.3%) or in combinations. Clarithromycin (SR 41.1%) and nitroxoline (SR 37.5%) were equally effective when compared to the current Lyme antibiotic cefuroxime (SR 36.8%) and more active than disulfiram. Cefuroxime + clarithromycin (SR 25.9%) and cefuroxime + nitroxoline (SR 27.5%) were significantly more active than cefuroxime + disulfiram (SR 41.7%). When replacing disulfiram with clarithromycin or nitroxoline in three-drug combinations, bacterial viability decreased significantly and subculture studies showed that combinations with these two drugs (cefuroxime + clarithromycin/nitroxoline + furazolidone/nitazoxanide) inhibited the regrowth, while disulfiram combinations did not (cefuroxime + disulfiram + furazolidone/nitazoxanide). Thus, clarithromycin and nitroxoline should be further assessed to determine their role as potential treatment alternatives in the future.

ABSTRACT Balamuthia mandrillaris is a pathogenic free-living amoeba that causes a rare but almost always fatal infection of the central nervous system called granulomatous amoebic encephalitis (GAE). Two distinct forms of B. mandrillaris—a proliferative trophozoite form and a nonproliferative cyst form, which is highly resistant to harsh physical and chemical conditions—have been isolated from environmental samples worldwide and are both observed in infected tissue. Patients suffering from GAE are typically treated with aggressive and prolonged multidrug regimens that often include the antimicrobial agents miltefosine and pentamidine isethionate. However, survival rates remain low, and studies evaluating the susceptibility of B. mandrillaris to these compounds and other potential therapeutics are limited. To address the need for more-effective treatments, we screened 2,177 clinically approved compounds for in vitro activity against B. mandrillaris. The quinoline antibiotic nitroxoline (8-hydroxy-5-nitroquinoline), which has safely been used in humans to treat urinary tract infections, was identified as a lead compound. We show that nitroxoline inhibits both trophozoites and cysts at low micromolar concentrations, which are within a pharmacologically relevant range. We compared the in vitro efficacy of nitroxoline to that of drugs currently used in the standard of care for GAE and found that nitroxoline is the most potent and selective inhibitor of B. mandrillaris tested. Furthermore, we demonstrate that nitroxoline prevents B. mandrillaris-mediated destruction of host cells in cultured fibroblast and primary brain explant models also at pharmacologically relevant concentrations. Taken together, our findings indicate that nitroxoline is a promising candidate for repurposing as a novel treatment of B. mandrillaris infections. IMPORTANCE Balamuthia mandrillaris is responsible for hundreds of reported cases of amoebic encephalitis, the majority of which have been fatal. Despite being an exceptionally deadly pathogen, B. mandrillaris is understudied, leaving many open questions regarding epidemiology, diagnosis, and treatment. Due to the lack of effective drugs to fight B. mandrillaris infections, mortality rates remain high even for patients receiving intensive care. This report addresses the need for new treatment options through a drug repurposing screen to identify novel B. mandrillaris inhibitors. The most promising candidate identified was the quinoline antibiotic nitroxoline, which has a long history of safe use in humans. We show that nitroxoline kills B. mandrillaris at pharmacologically relevant concentrations and exhibits greater potency and selectivity than drugs commonly used in the current standard of care. The findings that we present demonstrate the potential of nitroxoline to be an important new tool in the treatment of life-threatening B. mandrillaris infections.

Background: According to German AWMF S3 guideline nitroxoline is recommended as one of the first-choice antibiotics for treatment of acute uncomplicated cystitis (UC) in women. Under real-world conditions the clinical efficacy of nitroxoline should be checked in a noninterventional, prospective and multicenter study (NIS) and the prevalence of nitroxoline resistance in E. coli be monitored., Materials and Methods: Female patients with UC treated with nitroxoline (recommended dosage 250 mg tid for 5 days) were included by urologists, general practitioners (GPs), and internists in family medicine throughout Germany from April-December 2022 and followed for 21-28 days. The diagnosis and course of therapy were judged by the Acute Cystitis Symptom Score (ACSS) questionnaire and laboratory investigations (leukocyturia etc). Separately, a nationwide resistance surveillance was performed during 2019-2020 in collaboration with 23 laboratories to collect urinary E. coli isolates and test their susceptibility to nitroxoline., Results: Of the 316 patients with mean (SD) age of 57.2 (±20.4 [median 62.5]) years who were included in the NIS, 193/248 (86.3%) in the per-protocol group and in 193/263 (81.44%) in the intention-to-treat group were clinically successful. Furthermore, 96% of the patients rated the tolerability of nitroxoline as "very good" or "good". All 272 E. coli isolates tested were susceptible to nitroxoline., Conclusions: Nitroxoline showed very good clinical results in the NIS, and 100% of the tested E. coli urine isolates were susceptible to nitroxoline. Nitroxoline can still be recommended as one of the first-choice antibiotics for treatment of UC in women., (© 2023. The Author(s).)

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The severity of the SARS-CoV-2 pandemic and the recurring (re)emergence of viruses prompted the development of new therapeutic approaches that target viral and host factors crucial for viral infection. Among them, host peptidases cathepsins B and L have been described as essential enzymes during SARS-CoV-2 entry. In this study, we evaluated the effect of potent selective cathepsin inhibitors as antiviral agents. We demonstrated that selective cathepsin B inhibitors, such as the antimicrobial agent nitroxoline and its derivatives, impair SARS-CoV-2 infection in vitro. Antiviral activity observed at early stage of virus entry was cell-type dependent and correlated well with the intracellular content and enzymatic function of cathepsins B or L. Furthermore, tested inhibitors were effective against the ancestral SARS-CoV-2 D614 as well as against the more recent BA.1_4 (Omicron). Taken together, our results highlight the important role of host cysteine cathepsin B in SARS-CoV-2 virus entry and show that cathepsin-specific inhibitors, such as nitroxoline and its derivatives, could be used to treat COVID-19. Finally, these results also suggest that nitroxoline has potential to be further explored as repurposed drug in antiviral therapy. • Cathepsins are key host factors for SARS-CoV-2 entry. • Cathepsin B inhibitors are active against SARS-CoV-2. • Cathepsin activity is cell-type dependent. • The antibiotic nitroxoline is a candidate for drug repurposing. [ABSTRACT FROM AUTHOR]

The increasing resistance to antifungal agents associated with toxicity and interactions turns therapeutic management of fungal infections difficult. This scenario emphasizes the importance of drug repositioning, such as nitroxoline – a urinary antibacterial agent that has shown potential antifungal activity. The aims of this study were to discover the possible therapeutic targets of nitroxoline using an in silico approach, and to determine the in vitro antifungal activity of the drug against the fungal cell wall and cytoplasmic membrane. We explored the biological activity of nitroxoline using PASS, SwissTargetPrediction and Cortellis Drug Discovery Intelligence web tools. After confirmation, the molecule was designed and optimized in HyperChem software. GOLD 2020.1 software was used to predict the interactions between the drug and the target proteins. In vitro investigation evaluated the effect of nitroxoline on the fungal cell wall through sorbitol protection assay. Ergosterol binding assay was carried out to assess the effect of the drug on the cytoplasmic membrane. In silico investigation revealed biological activity with alkane 1-monooxygenase and methionine aminopeptidase enzymes, showing nine and five interactions in the molecular docking, respectively. In vitro results exhibited no effect on the fungal cell wall or cytoplasmic membrane. Finally, nitroxoline has potential as an antifungal agent due to the interaction with alkane 1-monooxygenase and methionine aminopeptidase enzymes, which are not the main human therapeutic targets. These results have potentially revealed a new biological target for the treatment of fungal infections. We also consider that further studies are required to confirm the biological activity of nitroxoline on fungal cells, mainly the confirmation of the alkB gene. [ABSTRACT FROM AUTHOR]

Nitroxoline is a chemotherapeutic which is used in acute and recurrent urinary tract infections (UTI) caused by Escherichia coli. The aim of the study was to estimate the sensitivity of strains that were isolated from urine to nitroxoline and to compare the results with sensitivity to co-trimoxazole and nitrofurantoin. Studies included 300 strains. Gram-negative rods constituted 93.0%, out of which 83.5% were E. coli and 7.0% were Gram-positive cocci. It was found that sensitivity of E. coli to nitroxoline was higher than to co-trimoxazole and nitrofurantoin. The sensitivity of other Gram-negative rods was varied and weak in the case of Gram-positive cocci. Varied sensitivity to nitroxoline of other rods from the Enterobacteriaceae family needs further research in order to perhaps widen the scope of indications for nitroxoline in UTI. [ABSTRACT FROM AUTHOR]

Equilibrium solubility data of nitroxoline in mixed solvents of (ethyl acetate + methanol), (ethyl acetate + ethanol), (ethyl acetate + n -propanol) and (ethyl acetate + isopropanol) were obtained experimentally by using the static method within the temperature range from (278.15 to 313.15) K under atmospheric pressure of 101.1 kPa. The mole fraction solubility of nitroxoline increased with increasing temperature and mass fraction of ethyl acetate. The obtained solubility data were mathematically represented by using five cosolvency models, including Jouyban–Acree model, van’t Hoff-Jouyban-Acree model, Apelblat-Jouyban-Acree model, Ma model, and Sun model. The maximum value of relative average deviation was 1.64 × 10 −2 , and root-mean-square deviation, 0.77 × 10 −4 . The dissolution process of nitroxoline in these mixed solvents was endothermic. The preferential solvation parameters were derived from their thermodynamic solution properties via the method of inverse Kirkwood–Buff integrals. The preferential solvation parameters for nitroxoline ( δx 1,3 ) were positive in intermediate compositions and ethyl acetate-rich mixtures but negative in alcohol-rich compositions. In the regions with intermediate composition, the preferential solvation magnitude of nitroxoline by the ethyl acetate is higher in {ethyl acetate (1) + ethanol (2)} mixtures than in the other solvent mixtures at 298.15 K. The higher solvation by ethyl acetate in intermediate compositions and in ethyl acetate-rich mixtures could be explained in terms of the higher basic behaviour of ethyl acetate interacting with the Lewis acidic groups of the nitroxoline. [ABSTRACT FROM AUTHOR]

Abstract: Bacterial pathogens that infect and kill plants are responsible for major crop damage (e.g. citrus canker). As is the case with human pathogens, bacterial species which are invasive to plants acquire resistance to common crop‐bactericidal agents. Herein we report the identification of nitroxoline and simple halogenated quinoline (HQ) antibacterial agents that demonstrate antibacterial activities against a panel of plant pathogens, including Xanthomonas citri and Burkholderia andropogonis. A subset of active analogues was identified from an in‐house library of 36 nitrogen‐containing heterocycles which our group previously evaluated against multiple human pathogenic bacteria (e.g., Staphylococcus aureus). In this report, we also demonstrate that the phytochemical gallic acid (GA) potentiates the antibacterial activity of select halogenated quinolines against multiple Xanthomonas strains, including Xcc 306. We also show that nitroxoline and HQ 1 alone and in combination with GA inhibit Xcc 306 infection in a plant model, demonstrating the potential these compounds have as crop‐bactericidal agents. [ABSTRACT FROM AUTHOR]

Bacterial biofilms are surface-attached communities of slow-growing or non-replicating bacteria tolerant to conventional antibiotic therapies. Although biofilms are known to occur in ca. 80% of all bacterial infections, no therapeutic agent has been developed to eradicate bacteria housed within biofilms. We have discovered that nitroxoline, an antibacterial agent used to treat urinary tract infections, displays broad-spectrum biofilm-eradicating activities against major human pathogens, including drug-resistant Staphylococcus aureus and Acinetobacter baumannii strains . In this study, the effectiveness of nitroxoline to eradicate biofilms was determined using an in vitro [minimum biofilm eradication concentration (MBEC) = 46.9 µM against A. baumannii ] and ex vivo porcine skin model (2–3 log reduction in viable biofilm cells). Nitroxoline was also found to eradicate methicillin-resistant S. aureus (MRSA) persister cells in non-biofilm (stationary) cultures, whereas vancomycin and daptomycin were found to be inactive. These findings could lead to effective, nitroxoline-based therapies for biofilm-associated infections. [ABSTRACT FROM AUTHOR]

Background: Yeasts are found in urine specimens relatively often, especially in the elderly and patients under treatment with broad spectrum antibiotics, i. e. especially in intensive care unit (ICU) patients. In some cases, the number of pathogens is very high, i. e. >105/ml. The clinical relevance of detecting Candida in urine is difficult to assess. In the German S3 guidelines it is apodictically stated that an ascending infection of the urinary tract by yeasts does not occur but this may undoubtedly happen in certain instances in patients at risk, for example in the elderly, in diabetic persons and in the case of foreign bodies in the urinary tract. A hematogenous spread of yeasts can lead to pyelonephritis, which accompanies candiduria. In rare cases this can be induced by prostatitis and epididymitis. Therapy is indicated in all cases when a urological manipulation is planned, particularly those with injury to the mucosal barrier, in order to prevent an intraoperative spread of pathogens.Aim: The antimicrobial agents suitable for therapy of candiduria are limited, namely flucytosine, amphotericin B, which is also used for irrigation and fluconazole.Material and Methods: The in vitro effect of nitroxoline on 100 isolates of yeasts from urine was tested by an agar diffusion test.Results: Nitroxoline exerted a good activity against all yeast isolates.Discussion: The antibiotic nitroxoline has a good antifungal activity. It achieves high concentrations in urine and in addition, it is effective at low pH as well as against pathogens in biofilms, which most antimycotics cannot achieve. Hence, nitroxoline is suitable for termination of candiduria. Foreign bodies in the urinary tract, on which biofilms are formed, should be removed whenever possible. [ABSTRACT FROM AUTHOR]