Multidrug-resistant Bacterial Infections Research Articles

Identifying Cell-Penetrating Peptides for Effectively Delivering Antimicrobial Molecules into Streptococcus suis.

Cell-penetrating peptides (CPPs) are promising carriers to effectively transport antisense oligonucleotides (ASOs), including peptide nucleic acids (PNAs), into bacterial cells to combat multidrug-resistant bacterial infections, demonstrating significant therapeutic potential. Streptococcus suis, a Gram-positive bacterium, is a major bacterial pathogen in pigs and an emerging zoonotic pathogen. In this study, through the combination of super-resolution structured illumination microscopy (SR-SIM), flow cytometry analysis, and toxicity analysis assays, we investigated the suitability of four CPPs for delivering PNAs into S. suis cells: HIV-1 TAT efficiently penetrated S. suis cells with low toxicity against S. suis; (RXR)4XB had high penetration efficiency with inherent toxicity against S. suis; (KFF)3K showed lower penetration efficiency than HIV-1 TAT and (RXR)4XB; K8 failed to penetrate S. suis cells. HIV-1 TAT-conjugated PNA specific for the essential gyrase A subunit gene (TAT-anti-gyrA PNA) effectively inhibited the growth of S. suis. TAT-anti-gyrA PNA exhibited a significant bactericidal effect on serotypes 2, 4, 5, 7, and 9 strains of S. suis, which are known to cause human infections. Our study demonstrates the potential of CPP-ASO conjugates as new antimicrobial compounds for combating S. suis infections. Furthermore, our findings demonstrate that applying SR-SIM and flow cytometry analysis provides a convenient, intuitive, and cost-effective approach to identifying suitable CPPs for delivering cargo molecules into bacterial cells.

Burden of Multidrug-Resistant Gram-Negative Bacterial Infections in a Tertiary Care Hospital

Multidrug-resistant (MDR) Gram-negative bacterial infections have emerged as a major public health concern. The aim of the present study was to detect the rate of infections due to MDR Gram-negative bacteria (GNB) in a tertiary care hospital, the rate of Carbapenemases and AmpC-β-lactamases production and the Antimicrobial susceptibility test pattern (AST) among MDR GNB. The rate of MDR GNB during the study period was 25.70%. Urine samples showed the highest contribution to the total MDR GNB. Among the total MDR GNB isolates, 166 were randomly selected and included in the present study. A higher rate of MDR GNB was reported among male patients (61.5%) compared to the females (38.5%) and most of them were from the patients aged between 61-70 years (30.7%). The most prevalent MDR GNB was Klebsiella pneumoniae 80 (48.12%), followed by Escherichia coli 43 (25.9%). AST of MDR GNB revealed their significant resistance to β-lactamases/β-lactamases inhibitors, cephalosporins, fluoroquinolones and carbapenem drugs (98%). Of 123 MDR Enterobacterales, 83% of them were found to be Metallo β-lactamase (MBLs) producers by mCIM and eCIM methods. Of 43 MDR non-fermenters, 29 (67.4%) of them were found to be carbapenemase producers by MHT. About 29.51% of MDR GNB isolates were found to be AmpC producers by AmpC disk test. A reliable and rapid phenotypic method to detect carbapenemases and AmpC β-lactamases among MDR GNB in a routine microbiology laboratory method is clinically important to guide antibiotic therapy and implementation of effective infection control practices.

Hybrid nanoparticles combining nanoselenium-mediated Carica papaya extract and trimethyl chitosan for combating clinical multidrug-resistant bacteria

Multidrug-resistant bacterial infections pose a significant threat to human health, prompting the exploration of innovative solutions. In this study, a new series of antibacterial hybrid nanoparticles (HNPs) were developed. The HNPs are based on a combination of selenium nanoparticles (SeNPs), synthesized using Carica papaya leaf extract, and chitosan (CS/SeHNPs) or trimethyl chitosan (TMC/SeHNPs), respectively. Comprehensive characterization using UV‐Vis, FTIR, XRD, SEM-EDX, DLS, TEM, and DSC confirmed the structure and properties of the developed HNPs. SeNPs, CS/SeHNPs, and TMC/SeHNPs showed average hydrodynamic size of 78.8, 91.3, and 122 nm, and zeta potentials of −6.35 mV, +32.8 mV, and +54.8 mV, respectively. Biological assessments were conducted, including antibacterial and antibiofilm assays against clinical strains (E. coli, S. aureus, and K. pneumoniae), along with antioxidant activity. TMC/SeHNPs demonstrated superior performance compared to SeNPs and CS/SeHNPs with the lowest minimum inhibition concentrations (MIC) against S. aureus and K. pneumoniae (3.9 μg/mL) and 62.5 μg/mL against E. coli in addition to robust antibiofilm activity. Furthermore, the TMC/SeHNPs exhibited potent DPPH free radical scavenging ability and demonstrated good biocompatibility, as evidenced by cell viability assays on HFB4 cells. Overall, TMC/SeHNPs emerged as promising candidates in nanomedicine, offering high antioxidant, antibacterial, and antibiofilm activities alongside excellent biocompatibility.

Dietary and water restriction leads to increased susceptibility to antimicrobial resistant pathogens.

Dehydration and malnutrition are common and often underdiagnosed in hospital settings. Multidrug-resistant bacterial infections result in more than 35,000 deaths a year in nosocomial patients. The effect of temporal dietary and water restriction (DWR) on susceptibility to multidrug-resistant pathogens is unknown. We report that DWR markedly increased susceptibility to systemic infection by ESKAPE pathogens. Using a murine bloodstream model of methicillin-resistant Staphylococcus aureus infection, we show that DWR leads to significantly increased mortality and morbidity. DWR causes increased bacterial burden, severe pathology, and increased numbers of phagocytes in the kidney. DWR appears to alter the functionality of these phagocytes and is therefore unable to control infection. Mechanistically, we show that DWR impairs the ability of macrophages to phagocytose multiple bacterial pathogens and efferocytose apoptotic neutrophils. Together, this work highlights the crucial impact that diet and hydration play in protecting against infection.

Antibacterial Photodynamic Therapy of the Metallosurfactant-Fluorescein Conjugate under Visible Light Illumination.

Antibacterial photodynamic therapy (APDT) has received increased attention as a treatment for multidrug-resistant bacterial infections caused by antibiotic abuse. However, photosensitizers used in APDT have disadvantages such as water insolubility, self-aggregation, and photobleaching. To address these limitations, metal complexes have been explored. However, the use of such complexes tends to confine their antibacterial effectiveness specific bacterial strains. In this study, we report iron (Fe)- and copper (Cu)-based metallosurfactants as unique moieties for antibacterial photodynamic therapy (PDT) under the illumination of visible light. Briefly, our formulated Fe and Cu metallosurfactants, when combined with a fluorescein photosensitizer, exhibit nearly 100% antibacterial efficacy. This high efficiency is primarily attributed to the enhanced generation of singlet oxygen using FL in the presence of metallosurfactants when targeting bacteria such as Escherichia coli and Staphylococcus aureus under laser light. In vitro experiments further confirmed the superior antimicrobial activity of these metallosurfactants against a diverse range of microbial cultures, encompassing Gram-negative and Gram-positive bacteria as well as fungi. This performance outpaces conventional surfactants like cetyltrimethylammonium chloride and cetylpyridinium chloride. The compelling results from MTT assays and flow cytometry endorsed the substantial enhancement in antimicrobial properties achieved through Fe and Cu doping, all without the need for additional secondary agents. Notably, this synergistic antibacterial approach using metallosurfactants in PDT holds significant promise for the elimination of various bacteria in vivo, with the added advantage of mitigating the emergence of multidrug resistance.

Antimicrobial, phytochemical, and antioxidant characterization of the leaf extracts of Clematis montana and Clematis grata

The worldwide emergence of multidrug-resistant bacterial infections among the population has impaired the existing effectiveness of antimicrobial treatments, necessitating the hunt for other alternatives. We aimed to find the antibacterial and antioxidant activities of Clematis montana and C. grata leaf extracts (both species have medicinal use among the local population). Extracts were assessed against four pathogenic bacterial strains (Escherichia coli, Salmonella typhi, Pseudomonas aeruginosa, and Staphylococcus aureus), through the agar well diffusion method. Total flavonoid content (TFC), total phenolic content (TPC), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity were quantified. Results suggested that all plant extracts, particularly those extracted with methanol, were potentially active in suppressing pathogenic bacterial growth (particularly against P. aeruginosa and E. coli) although their efficiency varied when compared to vancomycin. However, the antibacterial activity of methanolic extracts from both species was not greatly influenced by the method of extraction (maceration/soxhlet apparatus). TFC was significantly higher in the methanolic extracts of both species in comparison to the n-hexane extracts, whereas TPC and DPPH scavenging activity were detected to be highest in the methanolic extract from the leaves of C. grata. Our results suggested that the leaf extracts from both Clematis species, particularly the methanolic-based extract of C. montana, might serve as a promising source of an effective antibacterial agent.

Nontoxic and proteolytic-resistant self-assembled peptide dendrimer aggregates to combat multidrug-resistant gram-negative bacterial infections

Peptide-based antimicrobial biomaterials hold considerable promise to treat the prevalent infections caused by multidrug-resistant (MDR) pathogens. However, their clinical translation is hampered by high toxicity, proteolytic degradation, and poorly understood in vivo efficacy. Here, we present a novel multi-functional blocks intelligent combination approach to create low-toxicity and proteolytic-resistant self-assembled peptide dendrimer aggregates (SPDAs) that exhibit low-micromolar activity (≤4 μM) against gram-negative bacteria and MDR Escherichia coli. We investigated the in vivo biosafety of SPDAs and found that they were substantially less systemically toxic than polymyxin B at the same dose. In a peritonitis-sepsis mouse model, the SPDAs demonstrated significant in vivo therapeutic potential for the treatment of MDR E. coli infections. Importantly, the antimicrobial activity of the SPDAs was exerted via multimodal mechanism that included rapid plasma membrane rupture, interference with cellular growth and metabolism, and triggering reactive oxygen species accumulation. Collectively, SPDAs show tremendous promise in addressing the prevalent infections caused by MDR gram-negative pathogens, and these findings may offer unique insights that will inspire the development of novel peptide-based therapeutics.

IS1-mediated chromosomal amplification of the arn operon leads to polymyxin B resistance in Escherichia coli B strains.

Polymyxins [colistin and polymyxin B (PMB)] comprise an important class of natural product lipopeptide antibiotics used to treat multidrug-resistant Gram-negative bacterial infections. These positively charged lipopeptides interact with lipopolysaccharide (LPS) located in the outer membrane and disrupt the permeability barrier, leading to increased uptake and bacterial cell death. Many bacteria counter polymyxins by upregulating genes involved in the biosynthesis and transfer of amine-containing moieties to increase positively charged residues on LPS. Although 4-deoxy-l-aminoarabinose (Ara4N) and phosphoethanolamine (PEtN) are highly conserved LPS modifications in Escherichia coli, different lineages exhibit variable PMB susceptibilities and frequencies of resistance for reasons that are poorly understood. Herein, we describe a mechanism prevalent in E. coli B strains that depends on specific insertion sequence 1 (IS1) elements that flank genes involved in the biosynthesis and transfer of Ara4N to LPS. Spontaneous and transient chromosomal amplifications mediated by IS1 raise the frequency of PMB resistance by 10- to 100-fold in comparison to strains where a single IS1 element located 90 kb away from the end of the arn operon has been deleted. Amplification involving IS1 becomes the dominant resistance mechanism in the absence of PEtN modification. Isolates with amplified arn operons gradually lose their PMB-resistant phenotype with passaging, consistent with classical PMB heteroresistance behavior. Analysis of the whole genome transcriptome profile showed altered expression of genes residing both within and outside of the duplicated chromosomal segment, suggesting complex phenotypes including PMB resistance can result from tandem amplification events.IMPORTANCEPhenotypic variation in susceptibility and the emergence of resistant subpopulations are major challenges to the clinical use of polymyxins. While a large database of genes and alleles that can confer polymyxin resistance has been compiled, this report demonstrates that the chromosomal insertion sequence (IS) content and distribution warrant consideration as well. Amplification of large chromosomal segments containing the arn operon by IS1 increases the Ara4N content of the lipopolysaccharide layer in Escherichia coli B lineages using a mechanism that is orthogonal to transcriptional upregulation through two-component regulatory systems. Altogether, our work highlights the importance of IS elements in modulating gene expression and generating diverse subpopulations that can contribute to phenotypic polymyxin B heteroresistance.

A pharmacovigilance study of adverse events associated with polymyxins based on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database

ABSTRACT Background Polymyxins have been regarded as last-line treatment for multidrug-resistant gram-negative bacterial infections. Nonetheless, concerns regarding toxicity persist. This study aimed to explore and compare potential adverse events (AEs) between colistin and polymyxin B (PMB). Methods Polymyxins-related AEs were retrieved from the U.S. Food and Drug Administration Adverse Event Reporting System between 2004 and 2022. Potential signals were estimated by the reporting odds ratio (ROR), and subgroup analyses were preformed to adjust for potential factors in AEs with significant disproportionality. Results Analysis of 3,915 records involving 718 patients revealed a higher disproportionality of renal and urinary disorders (ROR 1.62, 95% CI 1.01–2.59) and acute kidney injury (ROR 1.75, 95% CI 1.07–2.87) with colistin treatment. Conversely, colistin exhibited a lower risk for neurotoxicity (ROR 0.47, 95% CI 0.30–0.73). Seven cases of skin hyperpigmentation were reported with PMB, whereas none were reported with colistin. Over 80% of cases involving polymyxin-related AEs occurred during the first two weeks of therapies, with a median onset time of 4.5 days. Conclusions Patients received colistin displayed a higher potential risk of nephrotoxicity but a lower risk of neurotoxicity. Clinicians should be vigilant in monitoring the AEs of hyperpigmentation disorders induced by PMB.

L-carnitine co-administration prevents colistin-induced mitochondrial permeability transition and reduces the risk of acute kidney injury in mice

Colistin is a polymyxin antibiotic currently experiencing renewed clinical interest due to its efficacy in the treatment of multidrug resistant (MDR) bacterial infections. The frequent onset of acute dose-dependent kidney injury, with the potential of leading to long-term renal damage, has limited its use and hampered adequate dosing regimens, increasing the risk of suboptimal plasma concentrations during treatment. The mechanism of colistin-induced renal toxicity has been postulated to stem from mitochondrial damage, yet there is no direct evidence of colistin acting as a mitochondrial toxin. The aim of this study was to evaluate whether colistin can directly induce mitochondrial toxicity and, if so, uncover the underlying molecular mechanism. We found that colistin leads to a rapid permeability transition of mitochondria isolated from mouse kidney that was fully prevented by co-incubation of the mitochondria with desensitizers of the mitochondrial transition pore cyclosporin A or L-carnitine. The protective effect of L-carnitine was confirmed in experiments in primary cultured mouse tubular cells. Consistently, the relative risk of colistin-induced kidney damage, calculated based on histological analysis as well as by the early marker of tubular kidney injury, Kim-1, was halved under co-administration with L-carnitine in vivo. Notably, L-carnitine neither affected the pharmacokinetics of colistin nor its antimicrobial activity against relevant bacterial strains. In conclusion, colistin targets the mitochondria and induces permeability transition thereof. L-carnitine prevents colistin-induced permeability transition in vitro. Moreover, L-carnitine co-administration confers partial nephroprotection in mice treated with colistin, without interfering with its pharmacokinetics and antibacterial activity.

An enterococcal phage protein broadly inhibits type IV restriction enzymes involved in antiphage defense.

The prevalence of multidrug resistant (MDR) bacterial infections continues to rise as the development of antibiotics needed to combat these infections remains stagnant. MDR enterococci are a major contributor to this crisis. A potential therapeutic approach for combating MDR enterococci is bacteriophage (phage) therapy, which uses lytic viruses to infect and kill pathogenic bacteria. While phages that lyse some strains of MDR enterococci have been identified, other strains display high levels of resistance and the mechanisms underlying this resistance are poorly defined. Here, we use a CRISPR interference (CRISPRi) screen to identify a genetic locus found on a mobilizable plasmid from Enterococcus faecalis involved in phage resistance. This locus encodes a putative serine recombinase followed by a Type IV restriction enzyme (TIV-RE) that we show restricts the replication of phage phi47 in E. faecalis. We further find that phi47 evolves to overcome restriction by acquiring a missense mutation in a TIV-RE inhibitor protein. We show that this inhibitor, termed type IV restriction inhibiting factor A (tifA), binds and inactivates diverse TIV-REs. Overall, our findings advance our understanding of phage defense in drug-resistant E. faecalis and provide mechanistic insight into how phages evolve to overcome antiphage defense systems.

Development of Novel Bacterial Topoisomerase Inhibitors Assisted by Computational Screening.

Multidrug-resistant bacterial infections pose an ever-evolving threat to public health. Since the outset of the antibacterial age, bacteria have developed a multitude of diverse resistance mechanisms that suppress the effectiveness of current therapies. New drug entities, such as Novel Bacterial Topoisomerase Inhibitors (NBTIs), can circumvent this major issue. A computational docking model was employed to predict the binding to DNA gyrase of atypical NBTIs with novel pharmacophores. Synthesis of NBTIs based on computational docking and subsequent antibacterial evaluation against both Gram-positive and Gram-negative bacteria yielded congeners with outstanding anti-staphylococcal activity and varying activity against select Gram-negative pathogens.

The power of trans-sodium crocetinate: exploring its renoprotective effects in a rat model of colistin-induced nephrotoxicity.

Colistin, a multidrug-resistant gram-negative bacterial infection medication, has been associated with renal impairment and failure. Trans-sodium crocetinate (TSC), a saffron-derived chemical recognized for its antioxidant and nephroprotective properties, was studied in this study to determine its potential to alleviate the nephrotoxic effects of colistin. Forty-two male Wistar rats were randomly classified into seven groups (n = 6): (1) control (normal saline, 12 days, i.p.), (2) colistin (22 mg/kg, 7 days, i.p.), (3-5) colistin + TSC (25, 50, and 100 mg/kg, 12 days, i.p., starting from 5 days before colistin), (6) TSC (100 mg/kg, 12 days, i.p.), (7) colistin + vitamin E (100 IU/kg, 12 days, i.p). On day 13, the rats were euthanized and the serum content of creatinine, BUN, Na+, and K+, as well as oxidative stress (GSH, MDA, SOD, CAT), inflammatory (IL-1β), apoptotic (Bax, Bcl-2, caspase-3, 8, 9), and autophagy (Beclin-1, LC3) markers, NGAL, and histopathological changes in the kidney were measured. Colistin significantly increased serum creatinine, BUN, MDA, IL-1β, caspase-3,8,9, Bax, Beclin-1, LC3, and NGAL levels in kidney tissue. It also caused inflammation, focal necrosis of tubular epithelial cells, protein cast, and acute tubular necrosis. Furthermore, colistin decreased SOD, CAT, GSH, and Bcl-2 levels. TSC and vitamin E administration along with colistin restored most of the alterations induced by colistin. Overall, it could be concluded that colistin induces oxidative stress, inflammation, autophagy, and apoptosis, which can cause kidney injury. However, TSC can also be used as a therapeutic agent to reduce injuries caused by colistin.

White light-driven enhanced cerium-doped carbon dots activity to combat multidrug-resistant bacterial infection

Infections caused by multidrug-resistant (MDR) bacteria are increasing and becoming an urgent global health crisis. The discovery and development of novel antibacterial agents to combat MDR are highly desirable. Here, we report the fabrication of cerium-doped carbon dots (CeCDs) with a simple hydrothermal method, which exhibit intrinsic broad efficacy against MDR bacteria including clinical isolates while maintaining low cytotoxicity and hemolytic effects. Importantly, the antibacterial activity of CeCDs is dramatically improved owing to the generation of reactive oxygen species (ROS) upon white light irradiation. Comprehensive analyses revealed that the CeCDs can penetrate the bacterial wall, disrupt the cell membrane, and prevent the biofilm formation, possibly hindering the bacterial resistance development. And the interaction of CeCDs with lipopolysaccharide (LPS) may contribute to the higher activity against Gram-negative bacteria strains. The treatment of CeCDs in a murine skin infection model can significantly reduce the number of bacteria on infected sites and accelerate wound healing by irradiation with light. Overall, CeCDs show great promise as low-cost and efficient antibacterial agents for chronic wounds and may be served as a powerful weapon to fight against the growing threat of MDR bacterial infection.

New Predictive Equation for the Estimation of Plasma Concentrations of Formed Colistin in Patients Treated With Colistimethate Sodium for Multidrug-Resistant Gram-Negative Bacterial Infections.

The clinical use of colistin methanesulphonate (CMS) is limited by potential nephrotoxicity. The selection of an efficient and safe CMS dose for individual patients is complicated by the narrow therapeutic window and high interpatient pharmacokinetic variability. In this study, a simple predictive equation for estimating the plasma concentration of formed colistin in patients with multidrug and extremely drug-resistant gram-negative bacterial infections was developed. The equation was derived from the largest clinical cohort of patients undergoing therapeutic drug monitoring (TDM) of colistin for over 8 years in a tertiary Spanish hospital. All variables associated with C ss,avg were selected in a multiple linear regression model that was validated in a second cohort of 40 patients. Measured C ss,avg values were compared with those predicted by our model and a previous published algorithm for critically ill patients. In total, 276 patients were enrolled [the mean age was 67.2 (13.7) years, 203 (73.6%)] were male, and the mean (SD) C ss,avg was 1.12 (0.98) mg/L. Age, gender, estimated glomerular filtration rate, CMS dose and frequency, and concomitant drugs were included in the model. In the external validation, the previous algorithm appeared to yield more optimized colistin plasma concentrations when all types of C ss,avg values (high and low) were considered, while our equation yielded a more optimized prediction in the subgroup of patients with low colistin plasma concentrations (C ss,avg <1.5 mg/L). The proposed equation may help clinicians to better use CMS among a wide variety of patients, to maximize efficacy and prevent nephrotoxicity. A further prospective PK study is warranted to externally validate this algorithm.

Dual phage-incorporated electrospun polyvinyl alcohol-eudragit nanofiber matrix for rapid healing of diabetic wound infected by Pseudomonas aeruginosa and Staphylococcus aureus.

Diabetic wound healing remains a healthcare challenge due to co-occurring multidrug-resistant (MDR) bacterial infections and the constraints associated with sustained drug delivery. Here, we integrate two new species of phages designated as PseuPha1 and RuSa1 respectively lysing multiple clinical MDR strains of P. aeruginosa and S. aureus into a novel polyvinyl alcohol-eudragit (PVA-EU†) nanofiber matrix through electrospinning for rapid diabetic wound healing. PVA-EU† evaluated for characteristic changes that occurred due to electrospinning and subjected to elution, stability and antibacterial assays. The biocompatibility and wound healing ability of PVA-EU† were assessed through mouse fibroblast cell line NIH3T3, followed by validation through diabetic mice excision wound co-infected with P. aeruginosa and S. aureus. The electrospinning resulted in the incorporation of ~ 75% active phages at PVA-EU†, which were stable at 25°C for 30days and at 4°C for 90days. PVA-EU† showed sustained release of phages for 18h and confirmed to be detrimental to both mono- and mixed-cultures of target pathogens. The antibacterial activity of PVA-EU† remained unaltered in the presence of high amounts of glucose, whereas alkaline pH promoted the activity. The matrix exerted no cytotoxicity on NIH3T3, but showed significant (p < 0.0001) wound healing in vitro and the process was rapid as validated through a diabetic mice model. The sustained release, quick wound closure, declined abundance of target MDR bacteria in situ and histopathological signs of recovery corroborated the therapeutic efficacy of PVA-EU†. Taken together, our data signify the potential application of PVA-EU† in the rapid treatment of diabetic wounds without the aid of antibiotics.

CTC-177, a novel drug-Fc conjugate, shows promise as an immunoprophylactic agent against multidrug-resistant Gram-negative bacterial infections.

The widespread emergence of antibiotic resistance including MDR in Gram-negative bacterial pathogens poses a critical challenge to the current antimicrobial armamentarium. To create a novel drug-Fc conjugate (DFC) that can be delivered at sustained and prolonged levels while simultaneously activating the host immune response to combat MDR Gram-negative infections. The Cloudbreak™ platform was used to develop DFCs consisting of a targeting moiety (TM) (a polymyxin-derived dimer) attached via a non-cleavable linker to an effector moiety (EM) (the Fc domain of human IgG1). In vitro activities of the DFCs were assessed by MIC testing. Neutropenic mouse models of thigh infection, septicaemia and pneumonia were used to evaluate in vivo efficacy. Pharmacokinetics were evaluated in mice and cynomolgus monkeys. A single prophylactic dose of our lead DFC, CTC-177, resulted in significantly decreased bacterial burdens and reduced inflammation comparable to daily treatment with colistin in septicaemia and pneumonia mouse models. Furthermore, CTC-177 prophylaxis was able to restore colistin efficacy in colistin-resistant septicaemia, reducing bacterial burdens beyond the limit of detection. Finally, CTC-177 displayed a long terminal half-life of over 24 and 65 h in mice and cynomolgus monkeys, respectively. These data support the continued development of Cloudbreak™ DFCs as broad-spectrum prophylactic agents against Gram-negative infections.

Bacteriophage therapy- a refurbished age-old potential strategy to treat antibiotic and multidrug resistant bacterial infections in future.

The worldwide prevalence of antimicrobial resistance coupled with the unavailability of newer antibiotics, has brought the sharp focus back among the scientific community, towards the discovery of novel alternative therapeutics to tackle the menace. Consequently, in the current post-antibiotic era, 'Bacteriophage Therapy' has emerged as one of the most promising option to address this problem. Bacteriophages, actually discovered long back, has shown greater potential to kill various bacterial pathogens, including the resistant clinical ones. Some of the other advantages for the use of bacteriophage therapy to treat infectious diseases include, wider availability of these microorganisms in nature, host-specific action, absence of any significant side-effects in humans and most often also exhibiting a broader anti-bacterial potential. In the recent times, the potential of phage therapy has been demonstrated in various treatments, clinical trials and infection models across the globe, where even antibiotics have completely failed. To address the global threat of AMR, WHO and UN have jointly illustrated "One Health" approach, recently extending the context to bacteriophage therapy. Many pharmaceutical companies have also recently started employing bacteriophages for developing different kinds of formulations for catering to medical and other industries. It has even shown great effect as combinatorial therapy along with antibiotics, to treat or manage various critical antibiotic resistant clinical infections. This continuously expanding potential of the bacteriophages holds great promise in the future, in the fight against the rising threat of AMR globally.

Significance of Triazole in Medicinal Chemistry: Advancement in Drug Design, Reward and Biological Activity.

One of the triazole tautomers, 1,2,4-triazole derivatives, has a wide range of biological activities that suggest its potential therapeutic utility in medicinal chemistry. These actions include anti-inflammatory, anti-cancer, anti-bacterial, anti-tuberculosis, and anti-diabetic effects. Using computational simulations and models, we investigate the structure-activity relationships of 1,2,4-triazoles, showing how various modifications to the triazole core yield a variety of clinical therapeutic benefits. The review highlights the anti-inflammatory effect of 1,2,4-triazoles in relation to their ability to disrupt significant inflammatory mediators and pathways. We present in-silico data that illuminate the triazoles' capacity to inhibit cell division, encourage apoptosis, and stop metastasis in a range of cancer models. This review looks at the bactericidal and bacteriostatic properties of 1,2,4-triazole derivatives, with a focus on their potential efficacy against multi-drug resistant bacterial infections and their usage in tuberculosis therapy. In order to better understand these substances' potential anti-diabetic benefits, this review also looks at how they affect glucose metabolism regulation and insulin responsiveness. Coordinated efforts are required to translate the efficacy of 1,2,4-triazole compounds in preclinical models into practical therapeutic benefits. Based on the information provided, it can be concluded that 1,2,4-triazole derivatives are a promising class of diverse therapeutic agents with potential utility in a range of disorders. Their development and improvement might herald a new era of medical care that will be immensely advantageous to both patients and the medical community as a whole. This comprehensive research, which is further reinforced by in-silico investigations, highlights the great medicinal potential of 1,2,4-triazoles. Additionally, this study encourages more research into these substances and their enhancement for use in pharmaceutical development.

Multidrug-resistant bacterial infections in the liver transplant setting.

Bacterial infections pose a life-threatening complication in patients with decompensated liver cirrhosis and acute-on-chronic liver failure. An increasing prevalence of infections caused by multidrug-resistant organisms (MDROs) has been observed in these patients, significantly impacting prognosis. A growing body of evidence has identified the most common risk factors for such infections, enabling the development of preventive strategies and therapeutic interventions. MDRO infections may also occur after liver transplantation (most commonly in the early post-operative phase), affecting both graft and patient survival. This review provides an overview of MDRO infections before and after liver transplantation, discussing epidemiological aspects, risk factors, prevention strategies, and novel therapeutic approaches. Furthermore, it examines the implications of MDRO infections in the context of prioritizing liver transplantation for the most severe patients, such as those with acute-on-chronic liver failure.