Conventional Drug Resistance Research Articles

Augmented cortisol and antiglucocorticoid therapy in mood disorders: the hippocampus as a potential drug target

The pathophysiology of many mood disorders is closely related to abnormal stress response associated with the dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and cortisol overproduction. The hippocampus, a key structure of the limbic system responsible for both cognitive and emotional spheres, is selectively vulnerable to excess of glucocorticoids (GCs) inducing neuroinflammation and neurodegeneration. The antiGC therapy of psychiatric diseases, in particular depressive disorders, may be a useful additional treatment. Among other approaches, targeting glucocorticoid receptors, abounded in the hippocampus, is regarded as highly promising. However, though the preclinical data provide fairly firm evidence to the concept of antiGC therapy for stress-related diseases, clinical studies still are at the proof-of-concept stage. Noteworthy, chronic GC excess is associated not only with mood diseases, but also with cognitive decline, metabolic disorders, diabetes. Potentially, antiGC (HPA axis modifying) therapy may alleviate affective symptoms, cognitive disturbances, GC and insulin resistance and adverse side effects of conventional drugs through beneficial effects on the hippocampus mitigating its dysfunction and neurodegeneration, neuroinflammation, and impairment of neurogenesis. Since stress/GC-associated neuroinflammation-mediated pathology of the limbic system and, specifically, the hippocampus, is a general feature typical for many brain diseases, the concept of antiGC therapy may be extended, tested and validated in a wider spectrum of cerebral pathologies.

Oestrogen receptor positive breast cancer and its embedded mechanism: breast cancer resistance to conventional drugs and related therapies, a review.

Traditional medication and alternative therapies have long been used to treat breast cancer. One of the main problems with current treatments is that there is an increase in drug resistance in the cancer cells owing to genetic differences such as mutational changes, epigenetic changes and miRNA (microRNA) alterations such as miR-1246, miR-298, miR-27b and miR-33a, along with epigenetic modifications, such as Histone3 acetylation and CCCTC-Binding Factor (CTCF) hypermethylation for drug resistance in breast cancer cell lines. Certain forms of conventional drug resistance have been linked to genetic changes in genes such as ABCB1, AKT, S100A8/A9, TAGLN2 and NPM. This review aims to explore the current approaches to counter breast cancer, the action mechanism, along with novel therapeutic methods endowing potential drug resistance. The investigation of novel therapeutic approaches sheds light on the phenomenon of drug resistance including genetic variations that impact distinct forms of oestrogen receptor (ER) cancer, genetic changes, epigenetics-reported resistance and their identification in patients. Long-term effective therapy for breast cancer includes selective oestrogen receptor modulators, selective oestrogen receptor degraders and genetic variations, such as mutations in nuclear genes, epigenetic modifications and miRNA alterations in target proteins. Novel research addressing combinational therapies including maytansine, photodynamic therapy, guajadiol, talazoparib, COX2 inhibitors and miRNA 1246 inhibitors have been developed to improve patient survival rates.

Mechanistic insight into the membrane disrupting properties of thymol in Candida species

Candida infection is a major problem in immunocompromised patients and has become a significant public health concern in recent years due to high toxicity, multidrug resistance and unfavourable side effects of conventional antifungal drugs. This study aims to investigate the antifungal efficacy of thymol, a natural monoterpenoid, on the membrane integrity of Candida albicans, Candida glabrata and Candida tropicalis. Minimum inhibitory concentrations (MICs) of thymol were 32 µg/ml, 63 µg/ml, and 125 µg/ml for C. albicans, C. tropicalis and C. glabrata, respectively. The minimum fungicidal concentrations (MFC) were 64 µg/ml, 110 µg/ml and 240 µg/ml, respectively. At MIC, thymol treated cells showed complete suppression of cell growth (growth kinetics, disc diffusion), altered morphology (scanning electron microscopy), leakage of intracellular macromolecules (absorption at 260 nm), significant reduction in ergosterol levels and inhibition of plasma membrane H+-ATPase (Pma1) activity. The disruption of the fungal membranes by thymol was further confirmed by propidium iodide uptake using flow cytometry and confocal microscopy. In silico studies with membrane-bound proteins (lanosterol 14-α demethylase (LDM) and Pma1), showed good binding affinity of −6.3 kcal/mol and −6.7 kcal/mol, respectively, and formed hydrogen bonds with crucial amino acid residues at the active site of target proteins. With low MIC values, negligible host toxicity, desirable ADME properties, thymol has immense potential as a potent antifungal drug that can be used for developing mechanism-based drugs as it has specific binding affinity for specific target proteins. Studies using animal models are required for further validation.

Effect of Succinamic Acid Derivative on the Growth Kinetics and Induction of Apoptosis in a Cancer Cell Line.

Introduction Head and neck cancers are heterogeneous malignancies associated with significant morbidity. Oral cancers are related to the use of tobacco products. Smokeless tobacco usage is a health problem worldwide, and its carcinogenic mechanism is largely unknown. Despite advances in conventional treatments, side effects and drug resistance remain unsolved. Therefore, novel therapeutic agents with minimal side effects using plant derivatives should be explored. An active antihyperglycemic and antioxidant compound known as FIIc was isolated from the fruit pulp of Eugenia jambolana (US Patent No.: 2,30,753). Although E. jambolana is reported to have anticancer activity, no study has been reported on its growth kinetics andapoptotic potential in the human head and neck cancer cell line (SCC4). The present study evaluated the effect of an herbal compound isolated from the fruit pulp of E. jambolana and chemically synthesized the same compound, α-hydroxy succinamic acid (α-HSA), on SCC4 proliferation and apoptotic gene expression. Methods The SCC4 cell line was cultured in Dulbecco's Modified Eagle Medium (DMEM). The dosages of smokeless tobacco extract (STE), herbal compound, and synthetic compound were determined by cell viability assay, and their effect on mRNA expression of apoptotic genes was measured by real-time polymerase chain reaction. Results The present study observed significant therapeutic effects of the natural and synthetic compounds from the fruit pulp of E. jambolana at the concentration range of 100-200 μg/mL on the SCC4 cell line. α-HSA had antiproliferative action; upregulated apoptotic genes like p53, p21, and Bax; and downregulated anti-apoptotic genes like survivin in the SCC4 cell line. Conclusion The therapeutic potential of α-HSA and the putative mechanisms involved may be explored to provide the basis for future therapeutic interventions in oral cancer mediated by smokeless tobacco.

Rational design and characterization of cell-selective antimicrobial peptides based on a bioactive peptide from Crocodylus siamensis hemoglobin

Antimicrobial resistance is a growing health concern. Antimicrobial peptides are a potential solution because they bypass conventional drug resistance mechanisms. Previously, we isolated a peptide from Crocodylus siamensis hemoglobin hydrolysate, which has antimicrobial activity and identified the main peptide from this mixture (QL17). The objective of this work was to evaluate and rationally modify QL17 in order to: (1) control its mechanism of action through bacterial membrane disruption; (2) improve its antimicrobial activity; and (3) ensure it has low cytotoxicity against normal eukaryotic cells. QL17 was rationally designed using physicochemical and template-based methods. These new peptide variants were assessed for: (1) their in vitro inhibition of microbial growth, (2) their cytotoxicity against normal cells, (3) their selectivity for microbes, and (4) the mode of action against bacteria using scanning electron microscopy (SEM), transmission electron microscopy (TEM) and confocal microscopy. The results indicate that all designed peptides have more potent antimicrobial efficacy than QL17 and IL15 peptides. However, only the most rationally modified peptides showed strong antimicrobial activity and minimal toxicity against normal cells. In particular, IL15.3 (hydrophobicity of 47% and net charge of + 6) was a potent antimicrobial agent (MIC = 4–12 μg/mL; MBC = 6–25 μg/mL) and displayed excellent selectivity for microbes (cf. human cells) via FACS assays. Microscopy confirmed that IL15.3 acts against bacteria by disrupting the cell membrane integrity and penetrating into the membrane. This causes the release of intracellular content into the outer environment leading to the death of bacteria. Moreover, IL15.3 can also interact with DNA suggesting it could have dual mode of action. Overall, a novel variant of QL17 is described that increases antimicrobial activity by over 1000-fold (~ 5 μg/mL MIC) and has minimal cytotoxicity. It may have applications in clinical use to treat and safeguard against bacteria.

Novel Inhibitors of androgen receptor's DNA binding domain identified using an ultra-large virtual screening.

Androgen receptor (AR) inhibition remains the primary strategy to combat the progression of prostate cancer (PC). However, all clinically used AR inhibitors target the ligand-binding domain (LBD), which is highly susceptible to truncations through splicing or mutations that confer drug resistance. Thus, there exists an urgent need for AR inhibitors with novel modes of action. We thus launched a virtual screening of an ultra-large chemical library to find novel inhibitors of the AR DNA-binding domain (DBD) at two sites: protein-DNA interface (P-box) and dimerization site (D-box). The compounds selected through vigorous computational filtering were then experimentally validated. We identified several novel chemotypes that effectively suppress transcriptional activity of AR and its splice variant V7. The identified compounds represent previously unexplored chemical scaffolds with a mechanism of action that evades the conventional drug resistance manifested through LBD mutations. Additionally, we describe the binding features required to inhibit AR DBD at both P-box and D-box target sites.

Azadiradione (AZD) neem biomass derived limonoid: extraction, characterization, and potential biological activities with special reference to anti-microbial and anti-cancer activities

The resistance of conventional drugs to bacterial infections and cancer poses a significant threat to the healthcare system causing increased mortality. Metabolites derived from plant biomass mainly medicinal plants exhibit a wide spectrum of biological activities with high efficacy and biocompatibility. Given the rising importance of using natural compounds as an antimicrobial and anticancerous agent, the current study aimed to determine the antibacterial and anticancerous properties of Azadiradione (AZD), neem-derived limonoid. The antibacterial property of AZD was determined against two important nosocomial pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa and the anticancer activity of AZD was analysed through evaluation of cytotoxicity in human colon cancer cell line (HCT-116). The Minimum inhibitory concentration (MIC) of AZD was found to be ≥6.25 µM and ≥25 µM for S. aureus and P. aeruginosa, respectively. The fluorescent assisted cell sorter (FACS) and scanning electron microscope (SEM) analysis have also revealed that AZD (100 µM) exhibits effective antibacterial activity. The AZD has also exhibited cytotoxicity, inhibited cell migration, increased ROS generation and superoxide levels, reduces mitochondrial membrane potential (MMP), and induces apoptosis in a concentration-dependent manner (25 µM - 100 µM) in human colon cancer cell lines. The highest concentration (100 µM) of AZD was found to arrest the Sub G1 and G0/G1 phase of the cell cycle, upregulates mRNA expression of pro-apoptotic proteins such as Bax, caspase-3, caspase-9 and downregulate anti-apoptotic protein- Bcl-2. Thus, AZD could be regarded as an effective anticancer antibiotic in future therapeutics.

Self-assembled nanocomposites of carboxymethyl β-dextran/protamine sulfate for enhanced chemotherapeutic drug sensitivity of triple-negative breast cancer by autophagy inhibition via a ternary collaborative strategy

Drug resistance in cancer chemotherapy is a major confounding factor affecting the effectiveness of chemotherapeutic agents, thereby leading to poor clinical outcomes. Most chemotherapeutic drugs can induce protective autophagy and increase the resistance of tumors to chemotherapeutic drugs and reduce effective drug delivery to tumor cells. In this study, a tri-drug nanocomposite (NP) delivery system was devised using carboxymethyl β-dextran (CMD) and protamine sulfate (PS), two natural materials with good bio-compatibility. They were designed to carry the chemotherapeutic drug docetaxel (DTX), the autophagy inhibitor chloroquine (CQ), and Atg5 siRNA to cancer cells. The CQ + DTX + Atg5 siRNA NPs was driven by electrostatic interaction and self-assembly methods. The breast cancer cell line MDA-MB-231 was used for both cell culture and establishing mouse xenograft model. Our findings demonstrated that CQ and Atg5 siRNA encapsulated in NPs could enhance the sensitivity of tumor cells to DTX. The NPs exhibited remarkable considerable therapeutic effects for treating triple-negative breast cancer (TNBC) and good biosafety. Therefore, we established a novel multifunctional nanoplatform based on CMD and PS that enhances chemotherapeutic drug sensitivity through an autophagy inhibition strategy, providing new opportunities to overcome conventional drug resistance and enhance therapeutic efficiency against TNBC.

Bioactive peptides for anticancer therapies.

Cancer is a serious concern in public health worldwide. Numerous modalities including surgery, radiotherapy, and chemotherapy, have been used for cancer therapies in clinic. Despite progress in anticancer therapies, the usage of these methods for cancer treatment is often related to deleterious side effects and multidrug resistance of conventional anticancer drugs, which have prompted the development of novel therapeutic methods. Anticancer peptides (ACPs), derived from naturally occurring and modified peptides, have received great attention in these years and emerge as novel therapeutic and diagnostic candidates for cancer therapies, because of several advantages over the current treatment modalities. In this review, the classification and properties of ACPs, the mode of action and mechanism of membrane disruption, as well as the natural sources of bioactive peptides with anticancer activities were summarised. Because of their high efficacy for inducing cancer cell death, certain ACPs have been developed to work as drugs and vaccines, evaluated in varied phases of clinical trials. We expect that this summary could facilitate the understanding and design of ACPs with increased specificity and toxicity towards malignant cells and with reduced side effects to normal cells.

Synthesis, characterization, computational studies and in vitro antiparasitic activity of novel flavanoidal-1,2,4,5-tetrazinane-6′-thione

Keeping in view the growing resistance of conventional antiparasitic drugs, this study aimed to synthesize a series of six noble flavanoidal tetrazinane-6′-thione derivatives by employing a facile one pot reaction pathway. Structural characterizations of synthesized compounds were performed by using IR, 1HNMR, 13CNMR and LC-MS spectra. Molecular docking study showed that one of the newly synthesized compounds strongly bind with the amino residues of BSA with two hydrogen bonding interactions. Physiological properties, pharmacokinetic properties (ADME) and toxicity of all synthesized compounds was carried out using Molinspiration and pkCSM softwares. DFT calculations were performed for all synthesized compounds using B3LYP method to obtain various molecular properties. Using a previously established model for parasitic infections, Clinostomum complanatum we showed that the newly synthesized compounds have a very potent parasitic activity. To elucidate the possible mechanisms, we tested the exposed parasites and observed a perturbation in lipid peroxidation and the antioxidant enzyme superoxide dismutase. Implications of this are discussed in the light of development of these molecules as antiparasitic drugs. HIGHLIGHTS Six noble flavanoidal-1,2,4,5-tetrazinane-6′-thiones (7–12) were synthesized using flavanone derivatives and thiocarbohydrazide in acetic acid as a reagent in ethanol employing one-pot synthesis. Structural characterization of synthesized compounds was done using IR, 1HNMR, 13CNMR and LC-MS spectra. Physicochemical analysis determined that all synthesized compounds are efficiently absorbed and have good permeability. In silico ADME and Toxic properties were determined for all synthesized compounds. In vitro antiparasitic activity was performed for all synthesized compounds against Clinostomum complanatum. Molecular Docking studies demonstrated the binding interaction with BSA enzyme through hydrogen bonding. Density functional theory (DFT) have been performed to estimate the various molecular properties of the synthesized compounds. Communicated by Ramaswamy H. Sarma

Repurposing of atorvastatin emulsomes as a topical antifungal agent

Cutaneous fungal infection therapy confronts several issues concerning skin permeation in addition to drug resistance and adverse effects of conventional drugs. The repurposing strategy is supposed to overcome some of those therapeutic obstacles. Recently, atorvastatin (ATO) revealed antifungal activity. ATO is an antihyperlipidemic drug with pH-dependent solubility, which limits skin permeation. This study aims to improve ATO antifungal activity by encapsulation in an emulsomes (EMLs) system, which seeks to ameliorate skin penetration. Therefore, multiple factors were investigated according to the One-Factor-at-a-Time (OFAT) design to achieve the optimum formula with targeted characteristics. Minimizing particle-size and polydispersity-index, besides elevating zeta-potential (ZP) and entrapment-efficiency were the desirable responses during assessing 11 factors. The selected ATO-EMLs formula (E21) recorded 250.5 nm in particle size, polydispersity index of 0.4, ZP of –25.93 mV, and 83.12% of drug entrapped. Morphological study of E21 revealed spherical core–shell vesicles in nanosize. DSC, XRD, and FTIR were conducted to discover the physicochemical properties and confirm emulsomes formation. Optimized ATO-EMLs slowed drug release rate as only 75% of ATO was released after 72 h. Stability study recommended storage between 2 and 8 °C. The in vivo permeation study remarked a homogeneous penetration of EMLs in different skin layers. The in vivo skin irritation test revealed limited histopathological changes. The in vitro and in vivo microbiological studies demonstrated a good antifungal activity of ATO-EMLs. ATO-EMLs system improved antifungal activity as the MIC values reduced from 650 µg/mL for free ATO to 550 µg/mL for ATO-EMLs. These findings may shed light on ATO as an antifungal drug and nanosystems as a tool to support drug repurposing.

PP2A Inhibitor LB100 Enhances the Sensitivity of NPM-ALK+ALCL to Crizotinib and Reverses the Resistance of ALCL to Crizotinib

Anaplastic large cell lymphoma (ALCL) is a rare and aggressive non-Hodgkin's lymphoma commonly discovered in children and adolescents. Despite the high remission rates in ALCL achieved by conventional chemotherapy based on conventional CHOP (cyclophosphamide, adriamycin, vincristine, prednisone), relapse and drug resistance occur in more than 40% of patients. The clinical use of the ALK inhibitor crizotinib in most relapsed refractory NPM-ALK+ ALCL in recent years has demonstrated effective treatment, but crizotinib resistance and intolerance due to the corresponding side effects still occur in 30% of cases. This urgently requires us to find new treatments to enhance the sensitivity of crizotinib as well as to overcome the resistance of crizotinib in ALCL. PP2A has been considered a tumor suppressor gene in the past, but with better understanding, it is two-sided, playing different roles in various types of tumors. In addition, it has been found that PP2A is closely related to drug sensitivity and resistance. LB100, a novel water-soluble PP2A inhibitor, is gaining attention because of its significantly higher safety profile than traditional PP2A inhibitors. It has potent effects on tumor inhibition and could increase tumor sensitivity to radiotherapy. In this study, we first established a crizotinib-resistant NPM-ALK+ ALCL cell model by exposing a highly sensitive NPM-ALK-positive ALCL cell line to continuously increasing doses of crizotinib until resistance developed. The PP2A inhibitor LB100 was then applied to normal and resistant cell lines to explore changes in their biological activity. We found that LB100 significantly inhibited the viability of normal and drug-resistant ALCL cell lines and was more sensitive in drug-resistant lines. In addition, a combination of LB100 and crizotinib was applied in normal and resistant cell lines to analyze the effect of LB100 on sensitization to crizotinib and reversal of drug resistance. LB100 significantly enhanced the killing effect of crizotinib in normal tumor cell lines and partially reverses crizotinib resistance in resistant lines. Western blot and immunofluorescence showed that LB100 leads to increased cellular G1 phase block by increasing cellular DNA damage, which in turn enhances the sensitivity of crizotinib. The above experiments showed that LB100, as an effective inhibitor of PP2A, can significantly increase the effect of crizotinib against normal NPM-ALK+ ALCL, inhibit the growth of crizotinib-resistant strains, and partially restore the sensitivity of crizotinib, which is expected to be a new therapeutic tool for ALCL. In addition, simultaneous targeting of PP2A and ALK has a very high potential in overcoming ALK inhibitor resistance in ALCL and could be a new therapeutic strategy to overcome drug resistance.

Dihydrotanshinone I Inhibits the Proliferation and Growth of Oxaliplatin-Resistant Human HCT116 Colorectal Cancer Cells.

Oxaliplatin (OXA) is a first-line chemotherapeutic drug for the treatment of colorectal cancer (CRC), but acquired drug resistance becomes the main cause of treatment failure. Increasing evidence has shown that some natural components may serve as chemoresistant sensitizers. In this study, we discovered Dihydrotanshinone I (DHTS) through virtual screening using a ligand-based method, and explored its inhibitory effects and the mechanism on OXA-resistant CRC in vitro and in vivo. The results showed that DHTS could effectively inhibit the proliferation of HCT116 and HCT116/OXA resistant cells. DHTS-induced cell apoptosis blocked cell cycle in S and G2/M phases, and enhanced DNA damage of HCT116/OXA cells in a concentration-dependent manner. DHTS also exhibited the obvious inhibition of tumor growth in the HCT116/OXA xenograft model. Mechanistically, DHTS could downregulate the expression of Src homology 2 structural domain protein tyrosine phosphatase (SHP2) and Wnt/β-catenin, as well as conventional drug resistance and apoptosis-related proteins such as multidrug resistance associated proteins (MRP1), P-glycoprotein (P-gp), Bcl-2, and Bcl-xL. Thus, DHTS markedly induces cell apoptosis and inhibits tumor growth in OXA-resistant HCT116 CRC mice models, which can be used as a novel lead compound against OXA-resistant CRC.

Antibacterial Efficacy of Hubballi Propolis against Aggregatibacter Actinomycetemcomitans One of the Major Causative Organisms of Perimplantitis: An In vitro Study.

Background:Peri-implantitis can be attributed to many underlying causes, one of the chief ones being due to infection caused by oral micro flora and particularly Aggregatibacter actinomycetemcomitans. Antibiotics are administered along with mechanical debridement to control the infection. The side effect of conventional antibiotic therapy and drug resistance has led to the necessity for alternate approaches to handle infections. Natural products are being investigated because of their multi-target activity and structurally different from the normal antibiotics. Propolis a product by Apis Mellifera bees as a wound healing and bone regenerating effect along with antimicrobial effect. One of the important features of Propolis is the chemical properties of Propolis changes with the different locations of procurement. Antimicrobial activity of Hubballi propolis against Aggregatibacter actinomycetemcomitans is not been reported in the literature.Aim:The aim of this study is to evaluate the antimicrobial effect of the Hubballi Propolis against Aggregatibacter actinomycetemcomitans.Methods:The two solvents used for the study were water and 70% Aq ethanol. Minimum inhibitory concentration (MIC), total phenolic contents (TPC), and total flavonoid content (TFC) were tested.Results:Hubballi Propolis sample showed antimicrobial effect against Aggregatibacter actinomycetemcomitans with MIC range from 0.1 mg/ml to 0.25 mg/ml.Conclusion:Hubballi Propolis is effective against Aggregatibacter actinomycetemcomitans infection thus may help in treating peri-implantitis. Propolis extracted with water as solvent showed better MIC, higher TPC and TFC than the propolis extracted using alcohol as solvent. This feature is noteworthy as the formulations produced using water extract is favorable than alcohol extract of propolis which irritates the mucosa and hence difficult for its application in dentistry.

Photothermal Therapy for the Treatment of Glioblastoma: Potential and Preclinical Challenges.

Glioblastoma (GBM) is a very aggressive primary malignant brain tumor and finding effective therapies is a pharmaceutical challenge and an unmet medical need. Photothermal therapy may be a promising strategy for the treatment of GBM, as it allows the destruction of the tumor using heat as a non-chemical treatment for disease bypassing the GBM heterogeneity limitations, conventional drug resistance mechanisms and side effects on peripheral healthy tissues. However, its development is hampered by the distinctive features of this tumor. Photoabsorbing agents such as nanoparticles need to reach the tumor site at therapeutic concentrations, crossing the blood-brain barrier upon systemic administration. Subsequently, a near infrared light irradiating the head must cross multiple barriers to reach the tumor site without causing any local damage. Its power intensity needs to be within the safety limit and its penetration depth should be sufficient to induce deep and localized hyperthermia and achieve tumor destruction. To properly monitor the therapy, imaging techniques that can accurately measure the increase in temperature within the brain must be used. In this review, we report and discuss recent advances in nanoparticle-mediated plasmonic photothermal therapy for GBM treatment and discuss the preclinical challenges commonly faced by researchers to develop and test such systems.

Medicinal chemistry updates on quinoline- and endoperoxide-based hybrids with potent antimalarial activity.

The resistance of conventional antimalarial drugs against the malarial parasite continues to pose a challenge to control the disease. The indiscriminate exploitation of the available antimalarials has resulted in increasing treatment failures, which urges on the search for novel lead molecules. Artemisinin-based combination therapy (ACT) is the current WHO-recommended first-line treatment for the majority of malaria cases. Hybrid molecules offer a newer strategy for the development of next-generation antimalarial drugs. These comprise molecules, each with an individual pharmacological activity, linked together into a single hybrid molecule. This approach has been utilized by several research groups to develop molecules with potent antimalarial activity. In this review, we provide an overview of the pivotal roles of quinoline- and endoperoxide-based hybrids as inhibitors of the life-cycle progression of Plasmodium. Based on the exhaustive literature reports, we have collated the structural and functional analyses of quinoline- and endoperoxide-based hybrid molecules that show potency equal to or greater than those of the individual compounds, offering an effective therapeutics option for clinical use.

Tuberculosis Resistance and Nanoparticles: Combating the Dual Role of Reactive Oxygen Species in Macrophages for Tuberculosis Management.

Increasing drift in antimicrobial therapy failure against Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), and the advent of extended resistant strains strongly demand discovery of mechanisms underlying development of drug resistance. The emergence of resistance against anti-TB drugs has reached an alarming level in various parts of the world, providing an active platform for the design of new targeted drug delivery. Reactive oxygen species (ROS) have an important role in controlling TB pathogenesis. At macrophage activation, ROS that are produced inside macrophages directly kill resident bacteria. These ROS possess a dual character because they can kill macrophages along with the resident bacteria. Targeting these ROS can play a remarkable part in overcoming resistance of conventional drugs. Nanoparticles (NPs) have evolved as a potential drug carrier for targeted delivery and elimination of various resistance mechanisms against antimicrobials. Receptor-mediated targeting of macrophages via different NPs may be a promising strategy for combating drug resistance and enhancing efficacy of old-fashioned antimycobacterial agents.

A MiSeq-HyDRA platform for enhanced HIV drug resistance genotyping and surveillance

Conventional HIV drug resistance (HIVDR) genotyping utilizes Sanger sequencing (SS) methods, which are limited by low data throughput and the inability of detecting low abundant drug resistant variants (LADRVs). Here we present a next generation sequencing (NGS)-based HIVDR typing platform that leverages the advantages of Illumina MiSeq and HyDRA Web. The platform consists of a fully validated sample processing protocol and HyDRA web, an open web portal that allows automated customizable NGS-based HIVDR data processing. This platform was characterized and validated using a panel of HIV-spiked plasma representing all major HIV-1 subtypes, pedigreed plasmids, HIVDR proficiency specimens and clinical specimens. All examined major HIV-1 subtypes were consistently amplified at viral loads of ≥1,000 copies/ml. The gross error rate of this platform was determined at 0.21%, and minor variations were reliably detected down to 0.50% in plasmid mixtures. All HIVDR mutations identifiable by SS were detected by the MiSeq-HyDRA protocol, while LADRVs at frequencies of 1~15% were detected by MiSeq-HyDRA only. As compared to SS approaches, the MiSeq-HyDRA platform has several notable advantages including reduced cost and labour, and increased sensitivity for LADRVs, making it suitable for routine HIVDR monitoring for both patient care and surveillance purposes.

Beyond multidrug resistance: Leveraging rare variants with machine and statistical learning models in Mycobacterium tuberculosis resistance prediction.

BackgroundThe diagnosis of multidrug resistant and extensively drug resistant tuberculosis is a global health priority. Whole genome sequencing of clinical Mycobacterium tuberculosis isolates promises to circumvent the long wait times and limited scope of conventional phenotypic antimicrobial susceptibility, but gaps remain for predicting phenotype accurately from genotypic data especially for certain drugs. Our primary aim was to perform an exploration of statistical learning algorithms and genetic predictor sets using a rich dataset to build a high performing and fast predicting model to detect anti-tuberculosis drug resistance.MethodsWe collected targeted or whole genome sequencing and conventional drug resistance phenotyping data from 3601 Mycobacterium tuberculosis strains enriched for resistance to first- and second-line drugs, with 1228 multidrug resistant strains. We investigated the utility of (1) rare variants and variants known to be determinants of resistance for at least one drug and (2) machine and statistical learning architectures in predicting phenotypic drug resistance to 10 anti-tuberculosis drugs. Specifically, we investigated multitask and single task wide and deep neural networks, a multilayer perceptron, regularized logistic regression, and random forest classifiers.FindingsThe highest performing machine and statistical learning methods included both rare variants and those known to be causal of resistance for at least one drug. Both simpler L2 penalized regression and complex machine learning models had high predictive performance. The average AUCs for our highest performing model was 0.979 for first-line drugs and 0.936 for second-line drugs during repeated cross-validation. On an independent validation set, the highest performing model showed average AUCs, sensitivities, and specificities, respectively, of 0.937, 87.9%, and 92.7% for first-line drugs and 0.891, 82.0% and 90.1% for second-line drugs. Our method outperforms existing approaches based on direct association, with increased sum of sensitivity and specificity of 11.7% on first line drugs and 3.2% on second line drugs. Our method has higher predictive performance compared to previously reported machine learning models during cross-validation, with higher AUCs for 8 of 10 drugs.InterpretationStatistical models, especially those that are trained using both frequent and less frequent variants, significantly improve the accuracy of resistance prediction and hold promise in bringing sequencing technologies closer to the bedside.

Emerging Mechanisms of Drug Resistance in Candida albicans.

Drug resistance mechanisms in the commensal human pathogen Candida albicans are continually evolving. Over time, Candida species have implemented diverse strategies to vanquish the effects of various classes of drugs, thereby emanating as a serious life threat. Apart from the repertoire of well-established strategies, which predominantly comprise permeability constraints, increased drug efflux or compromised drug import, alteration, overexpression of drug targets, and chromosome duplication, C. albicans has evolved novel regulatory mechanisms of drug resistance. For instance, recent evidences point to newer circuitry involving different mediators of the stress-responsive machinery of oxidative, osmotic, thermal, nitrosative, and nutrient limitation, which contribute to the emergence of drug resistance. Contemporary advances in genome-wide studies of transcription factors, for instance, the Zn2Cys6 transcription factors, TAC1 (transcriptional activator of CDR) in Candida albicans, or YRR1 in yeast have made it feasible to dissect their involvement for the elucidation of unexplored regulatory network of drug resistance. The coordination of implementers of the conventional and nonconventional drug resistance strategies provides robustness to this commensal human pathogen. In this review, we shed light not only on the established strategies of antifungal resistance but also discuss emerging cellular circuitry governing drug resistance of this human pathogen.