Search Results (18)

Background/Objectives: Simple urinary tract infections (sUTIs) are common in women and increasingly affected by multidrug-resistant (MDR) Escherichia coli. Extended-spectrum β-lactamase (ESBL) and AmpC producers restrict oral treatment options and promote carbapenem use. This study aimed to (i) describe the etiology and antimicrobial susceptibility of sUTIs in women of reproductive age in Oman, (ii) determine the prevalence of ESBL/AmpC-producing E. coli, (iii) evaluate nitroxoline, fosfomycin, mecillinam, and temocillin against ESBL and non-ESBL E. coli, and (iv) characterize circulating clones and resistance/virulence determinants using whole-genome sequencing (WGS). Methods: In this multicentric study (September 2022–August 2023), 795 uropathogens from 762 women (15–50 years) with sUTI were collected from four Omani hospitals. Identification and susceptibility testing of E. coli (n = 489) and Klebsiella pneumoniae (n = 140) using BD Phoenix and MALDI-TOF MS was performed (CLSI 2022). Thirty ESBL-producing and 82 non-ESBL E. coli underwent phenotypic ESBL/AmpC testing and evaluation of mecillinam, temocillin, nitroxoline, and fosfomycin. WGS was performed on 26 isolates (23 ESBL, 3 wild type) and analyzed for MLST, and SNP phylogeny using ResFinder, CARD, PlasmidFinder, VirulenceFinder. Statistical significance was set at p < 0.05. Results: E. coli (62%) and K. pneumoniae (18%) were the predominant pathogens. E. coli showed high susceptibility to nitrofurantoin (~97%), carbapenems, aminoglycosides, and piperacillin–tazobactam, but reduced susceptibility to cephalosporins, fluoroquinolones, cotrimoxazole, and ampicillin. ESBL prevalence ranged from 38–51%; AmpC producers were rare (4.6%). Mecillinam, nitroxoline, and fosfomycin exhibited 100% activity against both ESBL and non-ESBL isolates; temocillin showed 89.3% activity in ESBL strains. WGS identified 15 sequence types dominated by ST-131, ST-1193, ST-73, and ST-174, with blaCTX-M-15 as the major ESBL genotype. Conclusions: sUTIs in Oman show a high burden of ESBL-producing E. coli. Nitrofurantoin, mecillinam, fosfomycin, temocillin, and nitroxoline would be effective carbapenem-sparing oral options. Continuous phenotypic and genomic surveillance are crucial to guide antimicrobial therapy and stewardship. Full article

Background: Antimicrobial resistance is a major global challenge that is exacerbated by extensive antibiotic use in livestock farming. Identifying effective alternatives to widely used human antibiotics in animal production is vital to safeguard vital human medicines and ensure sustainable food systems. Here we describe studies identifying nitroxoline (NTX) as a promising antimicrobial candidate for use in poultry production. Methods: The antibacterial activity and resistance potential of NTX were assessed in vitro. In vivo studies in chickens evaluated tolerance, therapeutic efficacy in Salmonella-infected birds, pharmacokinetics, tissue residue depletion, growth performance, and effects on caecal microbiota. NTX was administered in-feed at different dose levels. Pharmacokinetic parameters and withdrawal periods were determined, and caecal microbiota composition was analysed using ribosomal RNA 16S sequencing. Results: NTX exhibits potent broad-spectrum antibacterial activity in vitro and low levels of resistance. NTX is well-tolerated in chickens at 500 mg/kg in-feed for 7 days and substantially reduces liver bacterial loads at 100 mg/kg in Salmonella-infected chickens. Pharmacokinetic and residue analyses reveal NTX manifests rapid absorption and distribution, high oral bioavailability (86%), and efficient tissue clearance with a 17-day withdrawal period required for skin-plus-fat clearance. NTX supplementation is associated with increased weight gain and improved feed efficiency compared to the control group, with performance comparable to chlortetracycline. Microbiota analysis indicates modulation of caecal bacterial communities, including increased Faecalibacterium and Lactobacillus. Conclusions: These results indicate that NTX is a viable alternative to important human antibiotics widely deployed in poultry production, offering a potential approach to minimise antimicrobial resistance whilst maintaining animal health and food biosafety. Full article

Monkeypox (Mpox) has re-emerged as a global public health threat, with recent outbreaks linked to novel mutations that enhance viral transmissibility and immune evasion. The Mpox virus (MPXV), a double-stranded deoxyribonucleic acid (DNA) orthopoxvirus, shares high structural and enzymatic similarity with the variola virus, underscoring the need for urgent therapeutic interventions. While conventional antiviral development is time-intensive and costly, drug repurposing offers a rapid and cost-effective strategy by leveraging the established safety and pharmacological profiles of existing medications. This is a narrative integrative review synthesizing published evidence on drug repurposing strategies against MPXV. To address these issues, this review explores MPXV molecular targets critical for genome replication, transcription, and viral assembly, highlighting how the Food and Drug Administration (FDA)-approved antivirals (cidofovir, tecovirimat), antibiotics (minocycline, nitroxoline), antimalarials (atovaquone, mefloquine), immunomodulators (infliximab, adalimumab), and chemotherapeutics (doxorubicin) have demonstrated inhibitory activity against the virus using computational or experimental approaches. This review further evaluates advances in computational methodologies that have accelerated the identification of host-directed and viral-directed therapeutic candidates. Nonetheless, translational challenges persist, including pharmacokinetic limitations, toxicity concerns, and the limited efficacy of current antivirals such as tecovirimat in severe Mpox cases. Future research should integrate computational predictions with high-throughput screening, organ-on-chip technologies, and clinical pipelines, while using real-time genomic surveillance to track viral evolution. These strategies establish a scalable and sustainable framework for the MPXV drug discovery. Full article

Background/Objectives: Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, remains a major neglected tropical disease, with over six million cases concentrated, primarily in Latin America. Despite decades of research, treatment continues to rely on two outdated drugs—benznidazole and nifurtimox—both of which exhibit limited efficacy and are associated with severe side effects. In this context, drug repurposing presents a promising strategy to accelerate the development of safer and more effective therapies. Nitroxoline, a hydroxyquinoline compound widely used in Europe to treat bacterial urinary tract infections, has recently garnered attention for its broad-spectrum antimicrobial and anticancer activities. This study evaluated the antitrypanosomal potential of nitroxoline against both epimastigote and intracellular amastigote forms of T. cruzi, demonstrating significantly greater efficacy than benznidazole. Methods: In addition to its antiparasitic activity, we investigated the mechanism of parasite death and found that nitroxoline induces hallmarks of programmed cell death, including chromatin condensation, mitochondrial membrane depolarization, ATP depletion, reactive oxygen species accumulation, and increased membrane permeability. These cellular events are critical for minimizing host tissue inflammation and suggest a safer therapeutic profile. Results: The nitroxoline was shown to induce greater activity than the reference treatment, benznidazole, in addition to triggering events related to apoptotic or silent cell death. Conclusions: Given its established clinical use and favorable safety data, nitroxoline emerges as a strong candidate for further investigation as a repurposed treatment for Chagas disease. Future work should focus on in vivo efficacy, pharmacokinetics, and drug delivery strategies to enhance systemic bioavailability. Full article

The threatening phenomenon of antibiotic failure in the future determines the intensive research of antibacterial active compounds, which are promising candidates as antibiotics. Quinolines, with only the representative in clinical practice being Nitroxoline^TM, are, in addition to being effective beta-lactams, macrolides, tetracyclines, and other antibiotic categories, forgotten antibiotics. The antibacterial efficiency of Nitroxoline^TM and 2-aminoquinolin-8-ol on eight selected highly resistant bacterial species that are the most problematic (Klebsiella ssp., Enterococcus ssp., Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus) could lead to higher solubility and thus bioavailability and increased antibacterial effects. In the first phase, the basic salts of Nitroxoline^TM, with sodium hydroxide, benzylamine, 4-(aminomethyl)pyridine, and other primary amines, were synthesized. In the second phase, the corresponding acidic salts of 2-aminoquinolin-8-ol were synthesized with the following acids: oxalic acid, pyrazine-2,3-dicarboxylic acid, chelidonic acid, quinaldic acid, 3,5-dinitrosalycilic acid, quinoline-2-carboxylic acid, quinoline-3-carboxylic acid, kynurenic acid, and xanthurenic acid. Nitroxoline^TM and 2-aminoquinolin-8-ol both demonstrated moderate antibacterial effects, with the average value for the eight mentioned bacterial strains being 16 mg/L (84 μM) and 50 mg/L (301 μM), respectively. The synthetized salts of both quinolinols demonstrated significantly higher solubility and slightly increased antibacterial activity. The identity and purity of the prepared products were determined by NMR and IR spectroscopy. The MW values of both quinolinols are relatively low and offer better use of the largest molecule limit, defined by Lipinski’s rule of five at 500 g/M. The options of amines and acids offer the achievement of quaternary salts with improved antibacterial activity. Full article

Recurrent cystitis in women represents an everyday challenge; however, little to no data regarding this population are available. This study aimed to evaluate this collective with respect to a rational calculated antibiotic therapy. Urine cultures and antibiograms from a urological office were retrospectively evaluated from patient data collected between January 2017 and June 2019. The evaluation was conducted using SPSS ©. In total, 84 female patients, who were aged between 18 and 87 years old (median 60 years), suffered from recurrent cystitis. Escherichia coli was found in 53.9% of cases, Staphylococcus aureus and enterococci were each found in 6.7%, and Proteus spp. and Streptococcus agalactiae were each found in 5.6%. The resistance levels to ciprofloxacin (CIP), trimethoprim–sulfamethoxazole (TRS), nitrofurantoin (NIT), and nitroxoline (NOX) were 18.2%, 30.7%, 16.1%, and 12.5% in the tested cases, respectively. Regarding E. coli, resistance to CIP, TRS, and NIT was found in 17.8%, 25%, and 4.2% of the tested cases, and no resistance to NOX was found. The resistance level to CIP was in a tolerable range of <20% in the overall cohort and the E. coli subgroup. More than a quarter of the bacteria were resistant to TRS. The low resistance rates for NIT and NOX are remarkable, promoting the use of these substances if they are not yet used. Full article

Enterococcus faecalis, responsible for a majority of human and nosocomial enterococcal infections, is intrinsically resistant to aminoglycoside antibiotics (such as gentamicin, GEN), which must be used in a combined therapy to be effective. Nitroxoline (NTX) is an old antibiotic, underused for decades, but rediscovered now in an era of growing antibiotic resistance. In this in vitro study, the types of interactions between NTX and GEN on 29 E. faecalis strains were analyzed with an aim to find synergistic antimicrobial and antiadhesion combinations. Transmission electron microscopy (TEM) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) were used to analyze changes in cell morphology and bacterial proteome after monotreatments and combined treatments. The results showed the synergistic effect for six combinations on eight strains, including the ATCC29212, and an additive effect for most strains. Combinations causing a complete inhibition of adhesion were established. Cell membrane integrity was affected by NTX, while combined NTX/GEN treatment caused dramatic changes in cell morphology. Upregulation of the expression of many proteins was established, with some emerging only after combined treatment. The results strongly imply that NTX has the potential for use in combined therapy with GEN against enterococci and it could further provide a substantial contribution to an ongoing fight against antimicrobial resistance and nosocomial infections. Full article

Diarrhoea remains an important public health concern, particularly in developing countries, and has become difficult to treat because of antibacterial resistance. The development of synergistic antimicrobial agents appears to be a promising alternative treatment against diarrhoeic infections. In this study, the combined effect of tetracycline together with either nitroxoline, sanguinarine, or zinc pyrithione (representing various classes of plant-based compounds) was evaluated in vitro against selected diarrhoeic bacteria (Enterococcus faecalis, Escherichia coli, Listeria monocytogenes, Shigella flexneri, Vibrio parahaemolyticus, and Yersinia enterocolitica). The chequerboard method in 96-well microtiter plates was used to determine the sum of the fractional inhibitory concentration indices (FICIs). Three independent experiments were performed per combination, each in triplicate. It was observed that the combination of tetracycline with either nitroxoline, sanguinarine, or zinc pyrithione produced synergistic effects against most of the pathogenic bacteria tested, with FICI values ranging from 0.086 to 0.5. Tetracycline–nitroxoline combinations produced the greatest synergistic action against S. flexneri at a FICI value of 0.086. The combinations of the agents tested in this study can thus be used for the development of new anti-diarrhoeic medications. However, studies focusing on their in vivo anti-diarrhoeic activity and safety are required before any consideration for utilization in human medicine. Full article

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. Full article

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. Full article

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. Full article

CBS encodes a pyridoxal 5′-phosphate-dependent enzyme that catalyses the condensation of homocysteine and serine to form cystathionine. Due to its implication in some cancers and in the cognitive pathophysiology of Down syndrome, the identification of pharmacological inhibitors of this enzyme is urgently required. However, thus far, attempts to identify such molecules have only led to the identification of compounds with low potency and limited selectivity. We consequently developed an original, yeast-based screening method that identified three FDA-approved drugs of the 8-hydroxyquinoline family: clioquinol, chloroxine and nitroxoline. These molecules reduce CBS enzymatic activity in different cellular models, proving that the molecular mechanisms involved in yeast phenotypic rescue are conserved in mammalian cells. A combination of genetic and chemical biology approaches also revealed the importance of copper and zinc intracellular levels in the regulation of CBS enzymatic activity—copper promoting CBS activity and zinc inhibiting its activity. Taken together, these results indicate that our effective screening approach identified three new potent CBS inhibitors and provides new findings for the regulation of CBS activity, which is crucial to develop new therapies for CBS-related human disorders. Full article

Introduction: Urinary tract infections (UTIs) are one of the most common infections both in the community and in the hospital setting. Aim: The aim of this study is to investigate the etiological spectrum and antimicrobial resistance of the most frequently isolated pathogens associated with UTIs in ambulatory patients in Varna city, Bulgaria during a seven-month period (October 2020–April 2021). Materials and methods: A total of 1600 urine samples, collected from patients with suspected UTIs were tested. Screening for bacterial growth was performed using an HB&L Uroquattro instrument (ALIFAX, Italy). Species identification and antimicrobial susceptibility testing were performed using a VITEK 2 Compact System (bioMerieux) and the Kirby–Bauer disk diffusion method. Results: A total of 127 urine samples (7.9%) were positive for bacterial growth using the HB&L. From these samples, 127 bacterial pathogens were isolated: Gram negative bacteria were found in 62.2% (n = 79) and Gram positive bacteria were found in 37.8% (n = 48). E. coli was the predominant species associated with UTIs in the group of patients studied (77%, n = 61). The Gram-positive bacteria accounted for 37.8% (n = 48), with E. faecalis being the leading pathogen in this group (87.5%, n = 42). Staphylococcus saprophyticus and Streptococcus agalactiae were diagnosed in 8% (n = 4) and 4% (n = 2), respectively. The resistance rates in the group of Gram-negative isolates (n = 79) in decreasing order were as follows: ampicillin, 64.5% > trimethoprim/sulfamethoxazole, 35.4% > ciprofloxacin, 29.1% > amoxicillin-clavulanic acid, 27.8% > cefuroxime, levofloxacin, 21.5% > fosfomycin, 12.6% > ceftriaxone, 13.9% > ceftazidime, 10.1% > gentamicin, nitrofurantoin, 6.3% > nitroxoline, 5%. The resistance rates among the isolates of E. faecalis (n = 42) were as follows: ciprofloxacin, 28.6% > gentamicin, 23.8% > levofloxacin, 19% > nitrofurantoin, 4.7% > amoxicillin, 2.4%. A low rate of third-generation cephalosporin resistance (ceftazidime, cefotaxime and ceftriaxone) was detected among the representative of order Enterobacterales in this study. The rates of ESBL-producing isolates, confirmed by the phenotypic DDST, were as follows: 5% in E. coli (n = 4), and 2.5% in K. pneumoniae (n = 2) and Enterobacter cloacae (n = 2). No resistance to meropenem, amikacin, vancomycin and teicoplanin was found in the collection of isolates studied (n = 127). Conclusion: The etiological spectrum of UTIs in ambulatory patients was dominated by E. coli, followed by E. faecalis. In the group of Gram-negative uropathogens, high resistance rates to ampicillin, trimethoprim/sulfamethoxazole and quinolones were detected. Third-generation cephalosporins, fosfomycin, nitrofurantoin and nitroxoline retained very good activity. Among the Enterococcus faecalis isolates, the second most commonly isolated bacterial species, decreased activity of the quinolones was found too, but the aminopenicillins and nitrofurantoin remained highly active. Full article

In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors. Pre-clinical experimental studies investigating the effects of various treatments (alone or combined) may discover how to overcome the immunotherapy-resistance in PC-patients. We performed a systematic literature review (PRISMA guidelines) to delineate the landscape of pre-clinical studies (including cell lines and mouse models) that tested treatments with effects on PD-L1 signaling in PC. NF-kB, MEK, JAK, or STAT inhibitors on human/mouse, primary/metastatic PC-cell lines variably down-modulated PD-L1-expression, reducing chemoresistance and tumor cell migration. If PC-cells were co-cultured with NK, CD8+ T-cells or CAR-T cells, the immune cell cytotoxicity increased when PD-L1 was downregulated (opposite effects for PD-L1 upregulation). In mouse models, radiotherapy, CDK4/6-inhibitors, and RB deletion induced PD-L1-upregulation, causing PC-immune-evasion. Epigenetic drugs may reduce PD-L1 expression. In some PC experimental models, blocking only the PD-1/PD-L1 pathway had limited efficacy in reducing the tumor growth. Anti-tumor effects could be increased by combining the PD-1/PD-L1 blockade with other approaches (inhibitors of tyrosine kinase, PI3K/mTOR or JAK/STAT3 pathways, p300/CBP; anti-RANKL and/or anti-CTLA-4 antibodies; cytokines; nitroxoline; DNA/cell vaccines; radiotherapy/Radium-223). Full article

The resistance of uropathogens to various antibiotics is increasing, but nitroxoline remains active in vitro against some relevant multidrug resistant uropathogenic bacteria. E. coli strains, which are among the most common uropathogens, are unanimously susceptible. Thus, nitroxoline is an option for the therapy of urinary tract infections caused by multiresistant bacteria. Since nitroxoline is active against bacteria in biofilms, it will also be effective in patients with indwelling catheters or foreign bodies in the urinary tract. Cotrimoxazole, on the other hand, which, in principle, can also act on bacteria in biofilms, is frequently inactive against multiresistant uropathogens. Based on phenotypic resistance data from a large number of urine isolates, structural characterisation of an MDR plasmid of a recent ST131 uropathogenic E. coli isolate, and publicly available genomic data of resistant enterobacteria, we show that nitroxoline could be used instead of cotrimoxazole for intervention against MDR uropathogens. Particularly in uropathogenic E. coli, but also in other enterobacterial uropathogens, the frequent parallel resistance to different antibiotics due to the accumulation of multiple antibiotic resistance determinants on mobile genetic elements argues for greater consideration of nitroxoline in the treatment of uncomplicated urinary tract infections. Full article