Search

A newly designed Pt(ii)–NHC complex shows potent activity against the Gram-positive S. aureus pathogen. Further investigation reveals biofilm inhibition, in vivo activity inside mammalian cells, and combinatorial antimicrobial activity with FDA-approved drugs.

Copper Pyrithione, [Cu(PyS)2] has shown excellent biological activity against cancer cells and bacterial cells, however, it has extremely low aqueous solubility, limiting its applicability. Herein, we report a series of PEG-substituted pyrithione copper(II) complexes with significantly increased aqueous solubility. While long PEG chains lead to a decrease in bioactivity, the addition of short PEG chains leads to improved aqueous solubility with retention of activity. One novel complex, [Cu(PyS1)2], has particularly impressive anticancer activity, surpassing that of the parent complex.

A cationic amphiphilic peptide effectively prevents the aggregation of soluble Aβ42 and also disintegrates matured fibrils into soluble precursors. In addition, the peptide also rescues cells from the toxicity of Aβ42.

Background: Drug repurposing is a viable approach to expediting the tedious conventional drug discovery process, given rapidly increasing bacterial resistance. In this context, we have repurposed pyrvinium pamoate (PP) for its antibacterial activity against Staphylococcus aureus. Methods: US FDA-approved non-antibiotics were screened against clinically relevant bacterial pathogens to identify antibacterials. The hits were further evaluated utilizing a variety of preclinical parameters, following which in vivo efficacy was estimated in isolation and in combination in a murine neutropenic thigh infection model. Result: The screening identified PP exhibiting potent activity against S. aureus along with concentration-dependent killing. PP also showed a post-antibiotic effect of >22 h and significantly eradicated preformed S. aureus biofilms and intracellular S. aureus at 1× and 5× MIC, respectively. PP synergized with levofloxacin both in vitro and in vivo, resulting in ∼1.5 and ∼0.5 log10 CFU/g reduction against susceptible and resistant S. aureus infections, respectively, as compared with untreated control. Conclusion: Pyrvinium potentiates levofloxacin against levofloxacin-resistant S. aureus.

Background: In the authors' previous study, 4-(2-((3-methyl-4-oxo-2-thioxo/dioxothiazolidin-5-ylidene) methyl) hydrazineyl) benzonitriles were found to demonstrate potent antibacterial activity against Acinetobacter baumannii. Interestingly, the aforementioned compounds contain a 4-cyanophenylhydrazine motif. Materials & methods: Intrigued by this observation, the authors focused on preparing a library of 4-cyanophenylhydrazine derivatives and studied their detailed antibacterial potential. Results: This study led to the identification of a 4-cyanophenylhydrazine with potent inhibitory activity against carbapenem-resistant A. baumannii BAA-1605, with minimum inhibitory concentration (MIC) of 0.25 μg/ml and highest selectivity index of 640. The compound also demonstrated potent inhibition against multidrug-resistant A. baumannii isolates (MIC: 0.25–1 μg/ml). Conclusion: The identified 4-cyanophenylhydrazine compound exhibited synergistic activity with amikacin, tobramycin and polymyxin B against carbapenem-resistant A. baumannii BAA-1605.

Discovery of novel antibiotics targeting multidrug-resistant (MDR) pathogens such as A. baumannii is an urgent, unmet medical need. Our work has highlighted the potential of this unique scaffold to annihilate MDR A. baumannii alone and in combination with amikacin both in vitro and in animals, that too without inducing resistance. Further in depth analysis identified central metabolism to be a putative target. Taken together, these experiments lay down the foundation for effective management of infections caused due to highly MDR pathogens.

During tuberculosis (TB) infection caused by Mycobacterium tuberculosis (Mtb), a sub-population of mycobacteria can enter a non-replicating persistent state that is not susceptible to most frontline TB drugs, resulting in phenotypic antimicrobial resistance (AMR), which contributes to an extended duration of TB therapy, frequent non-compliance and disease relapse. Recent clinical trial data indicated that inclusion of the fluoroquinolone Moxifloxacin (MXF) led to a shortening of TB treatment from 6-months to 4-months. MXF, however, has limited efficacy on Mtb persisting in a hypoxic environment. Here, we report a prodrug approach significantly enhancing lethality of MXF against non-replicating hypoxic Mtb while retaining its effectiveness against replicating Mtb. Since hypoxia is associated with a reductive environment and induces the expression of reductive enzymes such as nitroreducatases (NTRs) in Mtb, we designed and synthesized a library of nitroaryl and nitroheteroaryl conjugates of MXF. After optimization of several factors, including reduction potential, rate, and efficiency of drug release, as well as selectivity, we identified 2-nitrothiazole-derivative as a prodrug that is rapidly and nearly quantitatively converted to MXF in the presence of NTR. Biochemical studies supported by computational data reveal a rate-limiting influence of electron transfer in the mechanistic pathway for activation of the nitroaryl group, a key step in prodrug activation leading to drug release. The potency of lead prodrug against replicating bacteria in both cellular and animal model studies, and mode of action is nearly identical to MXF with significantly higher lethality against non-replicating Mtb than MXF. The prodrug showed improved accumulation of MXF inside non-replicating Mtb when compared with MXF alone, likely due to the ability of prodrug to enhance accumulation of MXF within non-replicating Mtb. Hence, together, the newly developed 2-nitrothiazole-prodrug is rapidly, efficiently, and selectively cleaved under reductive conditions to produce the active drug and had superior permeability and accumulation in non-replicating Mtb, which likely contributes to its increased efficacy. This proof-of-concept study supports prodrug approaches with a focus on improving accumulation of the active drug within non-replicating pathogens as a strategy to address phenotypic AMR.

Chemical investigation of roots of the plant, Rubia cordifolia Linn, led to the isolation of an undescribed anthraquinone, cordifoquinone R, determined as 1,2-dihydroxy-6-methoxyanthracene-9,10-dione (6) based on the 1D and 2D NMR analyses and HRESIMS. Ten other known compounds viz.1,4-dihydroxy-2-methoxyanthracene-9,10-dione (1), rubiadin (2), xanthopurpurin (3), 1-methoxy-3-hydroxy-2-carbomethoxy-9,10-anthraquinone (4), alizarin (5), β-sitosterol glucoside (7), scopoletin (8), oleanolic acid, (9), pomolic acid (10), queretaroic acid (11) were also isolated. Out of these compounds, 4, 10, and 11 are first reported from this plant species. Compounds 2, 3, 6, 7, and 10 showed activity in the range of 16-32 µg/ml against S. aureus ATCC 29213.

In our continued efforts to find potential chemotherapeutics active against drug-resistant (DR) Mycobacterium tuberculosis (Mtb), causative agent of Tuberculosis (TB) and to curb the current burdensome treatment regimen, herein we describe the synthesis and biological evaluation of urea and thiourea variants of 5-phenyl-3-isoxazolecarboxylic acid methyl esters as promising anti-TB agent. Majority of the tested compounds displayed potent in vitro activity not only against drug-susceptible (DS) Mtb H37Rv but also against drug-resistant (DR) Mtb. Cell viability test against Vero cells deemed these compounds devoid of significant toxicity. 3,4-Dichlorophenyl derivative (MIC 0.25 µg/mL) and 4-chlorophenyl congener (MIC 1 µg/mL) among urea and thiourea libraries respectively exhibited optimum potency. Lead optimization resulted in the identification of 1,4-linked analogue of 3,4-dichlorophenyl urea derivative demonstrating improved selectivity. Further, in silico study complemented with previously proposed prodrug like attributes of isoxazole esters. Taken together, this molecular hybridization approach presents a new chemotype having potential to be translated into an alternate anti-Mtb agent.

The genus

Antimicrobial resistance (AMR) is a global health concern. Targetting AMR, we present an

An amyloid-β inspired biocompatible short peptide amphiphile (sPA) molecule was used for controlled and targeted delivery of bioactive silver nanoparticles via transforming sPA nanostructures. Such sPA-AgNPs hybrid structures can be further used to develop antibacterial materials to combat emerging bacterial resistance. Due to the excellent antibacterial activity of silver, the growth of clinically relevant bacteria was inhibited in the presence of AgNPs-sPA hybrids. Bacterial tests demonstrated that the high biocompatibility and low cytotoxicity of the designed sPA allow it to work as a model drug delivery agent. It therefore shows great potential in locally addressing bacterial infections. The results of our study suggest that these nanodevices have the potential to trap and then engage in the facile delivery of their chemical payload at the target site, thereby working as potential delivery materials. This system has potential therapeutic value for the treatment of microbiota triggered progression of neurodegenerative diseases.

Background The dearth of antimicrobials to treat MDR infections has led to search for novel moieties with potent activity. The most suitable compounds have been derived from mainly natural sources. In this context, the current study focused on identification and determination of antistaphylococcal activity of malabaricone B (MB), one of the naturally abundant secondary metabolites (malabaricones A–D) present in the Myristicaceae family. Malabaricones have previously been reported to possess various biological activities including antimicrobial activity but prospects of its effective utilization against Staphylococcus aureus infections in particular have not been explored in detail to the best of our knowledge. Methods Malabaricones (A–D) were screened against an ESKAPE pathogen panel via broth microdilution assays. The hit compounds were then tested against Vero cells via MTT assays to determine their selectivity index. As the next step, their activity against clinical drug-resistant strains was evaluated. Further, time–kill kinetics against S. aureus were determined along with the ability to synergize with approved drugs via chequerboard assays, which was further validated via combination time–kill kinetics assays. The hit compound's in vitro post-antibiotic effect (PAE) and propensity to generate resistance to S. aureus was determined. Its activity against intracellular S. aureus in a J774 macrophage model of infection and ability to eradicate pre-formed S. aureus biofilms in vitro was ascertained. Finally, the hit compound's in vivo efficacy was determined in a murine neutropenic S. aureus thigh infection model. Results Amongst the hits identified, MB demonstrated a potent in vitro antistaphylococcal profile including equipotent activity against clinical MDR S. aureus and Enterococcus sp. with MIC 1–2 mg/L. MB exhibited concentration-dependent bactericidal activity with complete killing at 5 × MIC within 15 min of exposure with no regrowth up to 24 h. MB also displayed PAE of ∼22 h at 10 × MIC. It also has very low propensity for generation of resistance to S. aureus ATCC 29213. MB significantly eradicated pre-formed S. aureus biofilms and reduced intracellular S. aureus in the J774 macrophage infection model as well. MB strongly synergized with gentamicin at 1 × MIC in vitro with complete killing at 24 h as compared with untreated S. aureus. MB also possessed significant in vivo activity against S. aureus at 50 mg/kg BID dose with ∼0.5 log10 cfu/g reduction in thigh compared with untreated mice. Conclusions MB demonstrates the potential to be further developed for infections caused by S. aureus owing to its excellent in vitro and in vivo activity.

In pursuit of potent anti-TB agents active against drug resistant tuberculosis (DR-TB), herein we report synthesis and bio-evaluation of a new series of isoxazole-carboxylic acid methyl ester based 2-substituted quinoline derivatives. Preliminary evaluation indicated selectivity towards Mtb H37Rv, with no inhibition of non-tubercular mycobacterial (NTM)bacterial pathogen panel. Out of 36 synthesized compounds, majority exhibited substantial inhibition of Mtb H37Rv (MIC 0.5-8 μg/mL). Cell viability test against Vero cells revealed no significant cytotoxicity. Further, screening against drug resistant strains (DR-Mtb) found hit compound displaying promising potency (MIC 1-4 μg/mL). Structure optimization of the hit led to the identification of lead compound demonstrating potent inhibition of both drug-susceptible Mtb (MIC 0.12 μg/mL) and drug-resistant Mtb (MIC 0.25-0.5 μg/mL) along with a high selectivity index (SI)80. Taken together, with appreciable selectivity and potent activity, these chemotypes show prospect to be turned into a potential anti-TB candidate.

Antimicrobial resistance is a serious challenge to modern medicine. Besides imposing high financial burden, multidrug resistant infections are directly responsible for high morbidity and mortality. Even though a number of antibiotics are currently available to treat infections caused by ESKAPE organisms, more and more bacterial strains are becoming resistant to these drugs. Prevailing circumstances pose an urgent unmet need for the development of newer antimicrobials to treat the infections caused by MDR organisms. Rhodanine and structurally related 5-membered heterocycles possess wide range of pharmacological activities. A number of these derivatives have shown good to potent inhibition against various microorganisms. They are reported to alter the function of DNA gyrase B, metallo-β-lactamases, penicillin binding protein (PBP), Mur ligases, RNA polymerase, Enoyl ACP reductases, 1-deoxy-d-xylulose-5-phosphate reductoisomerase. etc which are vital in bacterial growth, survival and replication. In this study, we have generated a library of Rhodanine and related 5 membered heterocyclic derivatives and screened them against a panel of pathogens. Among all the compounds, 2a-i, 3a-b, 3g, 4, 6b-c, 6e, 6g, 12a-b and 14b-c have demonstrated good to moderate inhibition against S. aureus (MIC 0.125-8 μg/mL). Further, compound 17b demonstrated moderate activity against A. baumannii (MIC 8 μg/mL). In addition, compounds 2a, 2e, 4, 6c, 6g and 14b have shown good to mild inhibition against MDR S. aureus including VRSA (MIC 0.5-16 μg/mL) with good selectivity index 20-1600. In addition, compound 2e inhibited the growth gradually after 6 h in time kill kinetic studies and not antagonized with the tested FDA approved drugs.

Background Antimicrobial resistance is a growing menace, claiming millions of lives all over the world. In this context, drug repurposing is one approach gaining interest as a suitable alternative to conventional drug discovery and development. Methods Whole-cell assays were used to screen FDA-approved drugs to identify novel antimicrobial agents active against bacterial pathogens. Following identification of nitazoxanide, its various characteristics, such as antimicrobial activity against MDR isolates, time–kill kinetics, ability to synergize with approved drugs, antibiofilm activity and ability to generate resistance in Staphylococcus aureus, were determined, followed by determination of its in vivo potential against MDR S. aureus. Results Nitazoxanide demonstrated a potent in vitro antistaphylococcal profile, including equipotent activity against clinical drug-resistant S. aureus and Enterococcus spp. Nitazoxanide exhibited concentration-dependent killing, significantly eradicated preformed S. aureus biofilm and S. aureus did not generate resistance to it. Nitazoxanide strongly synergized with linezolid both in vitro and in vivo against linezolid-susceptible and -resistant S. aureus, displaying superior activity to untreated control and drug-alone treatment groups. Conclusions Nitazoxanide can be utilized in combination with linezolid against infections caused by linezolid-resistant S. aureus as it exhibits strong synergism in vitro and in vivo.

Green and facile synthesis of 24 tryptanthrin-thiopyrano[2,3-b]indole hybrid molecules is described (i) by a thermal one-pot multi-component strategy, (ii) using ammonium acetate in solvent-free conditions at 100 °C and (iii) by electrochemical method at room temperature. The in vitro antibacterial activities of compounds were evaluated against bacterial pathogen panel including clinically relevant highly drug-resistant MRSA/VRSA isolates, which led to the identification of nitro-substituted hybrid molecule 4c as being the most potent molecule against S. aureus ATCC 29213 with a high selectivity index. Upon further analysis, 4c exhibited concentration dependent bactericidal activity with a long PAE (post-antibiotic effect) and synergized with linezolid against S. aureus. From the in vitro metabolic stability assay (using rat liver microsomes) it was found that 4c has half-life of120 min. The co-crystallographic studies indicated that amino group in compound 4c is the potential binding site. From all the studies, it was clear that compound 4c exhibits all the hallmarks for positioning it as a novel anti-staphylococcal therapeutic option.

The quinoline moiety remains a privileged antitubercular (anti-TB) pharmacophore, whereas 8-nitrobenzothiazinones are emerging potent antimycobacterial agents with two investigational candidates in the clinical pipeline. Herein, we report the synthesis and bioevaluation of 30 piperazinyl-benzothiazinone-based quinoline hybrids as prospective anti-TB agents. Preliminary evaluation revealed 24/30 compounds exhibiting substantial activity (minimum inhibitory concentration [MIC] = 0.06-1 µg/ml) against Mycobacterium tuberculosis (Mtb) H37Rv. Cytotoxicity analysis against Vero cells found these to be devoid of any significant toxicity, with the majority displaying a selectivity index of80. Furthermore, potent nontoxic compounds, when screened against clinical isolates of drug-resistant Mtb strains, demonstrated equipotent inhibition with MIC values of 0.03-0.25 µg/ml. A time-kill study identified a lead compound exhibiting concentration-dependent bactericidal activity, with 10× MIC completely eliminating Mtb bacilli within 7 days. Along with acceptable aqueous solubility and microsomal stability, the optimum active compounds of the series manifested all desirable traits of a promising antimycobacterial candidate.

Ever increasing drug resistance has become an impeding threat that continues to hamper effective tackling of otherwise treatable tuberculosis (TB). Such dismal situation necessitates identification and exploration of multitarget acting newer chemotypes with bactericidal efficacy as a priority, that could efficiently hinder uncontrolled spread of TB. In this context, herein we present design, synthesis and bio-evaluation of chalcone tethered bezoxazole-2-amines as promising anti-TB chemotypes. Preliminary screening of 24 compounds revealed initial hits 3,4,5-trimethoxyphenyl and 5-nitrofuran-2-yl derivative exhibiting selective inhibition of Mycobacterium tuberculosis (Mtb) H37Rv. Further, structural optimization of hit compounds generated 12 analogues, amongst which 5-nitrofuran-2-yl derivatives displayed potent inhibition of not only drug-susceptible (DS) Mtb but also clinical isolates of drug-resistant (DR) Mtb strains equipotently. Moreover, cell viability test against Vero cells found these compounds with favourable selectivity. Time kill analysis led to the identification of the lead compound (E)-1-(4-((5-chlorobenzo[d]oxazol-2-yl)amino)phenyl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one, that demonstrated bactericidal killing of Mtb bacilli. Together with acceptable microsomal stability, the lead compound of the series manifested all desirable traits of a promising antitubercular agent.