Global Drug Resistance Research Articles

Optimizing Third Party Funding to Alleviate Global Drug Resistance: A Game-Theoretic Modelling Approach

Optimizing Third Party Funding to Alleviate Global Drug Resistance: A Game-Theoretic Modelling Approach

Antimicrobial susceptibility patterns of urinary tract infections causing bacterial isolates and associated risk factors among HIV patients in Tigray, Northern Ethiopia

BackgroundUrinary tract infections, a prevalent global infectious disease, are clinical issues not well studied in HIV-positive individuals. UTIs have become a global drug resistance issue, but the prevalence and antibiotic susceptibility patterns of UTI-causing bacteria among HIV patients in Tigray, Ethiopia, are poorly understood. This study aims to identify the prevalence of UTI-causing bacteria, their antibiotic susceptibility patterns, and associated risk factors in HIV patients attending ART clinics at Mekelle General Hospital and Ayder Comprehensive Specialized Hospital in Tigray, Northern Ethiopia.MethodClean-catch midstream urine samples (10–15 mL) were collected from HIV patients who are attending ART clinics at Mekelle General Hospital and Ayder Comprehensive Specialized Hospital. Samples were analyzed based on standard microbiological protocols using cysteine-lactose electrolyte deficient (CLED) agar. Pure colonies of bacterial isolates were obtained by sub-culturing into Mac-Conkey, Manitol Salt agar and blood agar plates. The bacterial isolates were then identified using macroscopic, microscopic, biochemical, and Gram staining methods. Gram-negative bacteria were identified using biochemical tests like triple sugar iron agar, Simon’s citrate agar, lysine iron agar, urea, motility test, and indol test, whereas Gram-positive isolates were identified using catalase and coagulase tests. The Kirby-Bauer disk diffusion technique was used to analyze the antimicrobial susceptibility pattern of bacterial isolates. Data was analyzed using SPSS version 25.0.ResultsAmong the 224 patients, 28 (12.5%) of them had been infected by UTIs-causing bacteria. E. coli was the dominant bacterium (16 (57%)) followed by K. pneumoniae (4 (14%)), and S. aureus (3 (11%)). Of the total bacterial isolates, 22 (78.6%) of them developed multi-drug resistance. All Gram-positive (100%) and 75% of Gram-negative bacterial isolates were found to be resistant to two or more drugs. Patients with a history of UTIs, and with CD4 count < 200 cells/ mm3, were more likely to have significant bacteriuria. Compared to male patients, female patients were more affected by the UTIs-causing bacteria. More than 93% of the UTIs-causing bacterial isolates were susceptible to nitrofurantoin, ceftriaxone, ciprofloxacin, and gentamycin; whereas they are highly resistant to ampicillin (96%), cotrimoxazole (82%) and tetracycline (71%).ConclusionsMost of the bacterial isolates were highly resistant to ampicillin, cotrimoxazole, and tetracycline. Female patients were more affected by the UTIs causing bacteria. The highest prevalence (12.5%) of UTIs in HIV patients needs special attention for better management and monitoring. Previous UTI history and immune suppression are predictors of UTIs, highlighting the need for intervention measures involving molecular studies to identify resistant bacteria genes and promote patient immune reconstitution.

Detection of drug-resistant malaria in resource-limited settings: efficient and high-throughput surveillance of artemisinin and partner drug resistance.

Artemisinin-resistant Plasmodium falciparum malaria is currently spreading globally, including in Africa. Artemisinin resistance also leads to resistance to partner drugs used in artemisinin-based combination therapies. Sequencing of kelch13, which is associated with artemisinin resistance, culture-based partner drug susceptibility tests, and ELISA-based growth measurement are conventionally used to monitor resistance; however, their application is challenging in resource-limited settings. An experimental package for field studies with minimum human/material requirements was developed. First, qPCR-based SNP assay was applied in artemisinin resistance screening, which can detect mutations within 1 h and facilitate sample selection for subsequent processes. It had 100% sensitivity and specificity compared with DNA sequencing in the detection of the two common artemisinin resistance mutations in Uganda, C469Y and A675V. Moreover, in the partner drug susceptibility test, the cultured samples were dry-preserved on a 96-well filter paper plate and shipped to the central laboratory. Parasite growth was measured by ELISA using redissolved samples. It well reproduced the results of direct ELISA, reducing significant workload in the field (Pearson correlation coefficient: 0.984; 95% CI: 0.975-0.990). Large-scale and sustainable monitoring is required urgently to track rapidly spreading drug-resistant malaria. In malaria-endemic areas, where research resources are often limited, simplicity and feasibility of the procedure is especially important. Our approach combines a qPCR-based rapid test, which is also applicable to point-of-care diagnosis of artemisinin resistance and centralized analysis of ex vivo culture. The approach could improve efficiency of field experiments and accelerate global drug resistance surveillance.

Targeted Development of Pyrazoline Derivatives for Neurological Disorders: A Review

AbstractPyrazolines are preferred to be stable heterocycles in medication development. It has been established from previous research that the 2‐pyrazolone scaffold is a common pattern that can be found in many pharmacologically significant therapeutic compounds. They are said to have a wide range of biological actions and have been thoroughly investigated by the scientific community. 2‐pyrazoline has been used as an intriguing pharmacophore to create novel compounds with enhanced potency, less toxicity, and the necessary pharmacokinetic profile to treat unprecedented diseases and global drug resistance. Experiments done by docking confirmed the hypothesized neuropharmacological mode of action and demonstrated a strong affinity towards the monoamine oxidase, β‐amyloid plaques, and AChE. Furthermore, additional computational pharmacokinetic assessments signify that it may not have any significant risk of carcinogenic effects, neurotoxic effects, reproductive intoxication, acute toxicity, mutagenicity, or irritations suggesting their possible utility in depressive, convulsions, and anxiety disorders. This discussion outlines a reliable approach for medicinal chemists to develop pyrazolines for the establishment of neurodegenerative research as well as future research programs on neurodegenerative disorders.

Optimizing solid-state fermentation for metabolite enrichment by Aspergillus tamarii on rice bran and wheat

Globalization has led to an increase in the global population and drug resistance, necessitating the development of novel pharmaceuticals. Fungi represent a promising source for new drugs, producing a diverse array of secondary metabolites, some of which are integral to clinically essential drugs. This study aimed to determine the optimal conditions for enhancing metabolite production by the Indonesian fungal strain Aspergillus tamarii (IPBCC 880066) when cultivated on solid media, specifically rice bran and wheat. The optimal fermentation conditions, including moisture content, growth temperature, and incubation duration, were determined based on the number of spots observed on thin-layer chromatography plates. Results indicated that the optimum conditions for metabolite production were a 40% moisture content, a growth temperature of 25°C, and a 14-day incubation period. Subsequent UPLC-MS/MS analysis identified 22 metabolites produced by A. tamarii on rice bran and 20 metabolites on wheat. Notably, two compounds, N-(2-hydroxypropyl)-2-methylacrylamide and N6-[(benzyloxy)carbonyl]-L-lysine, were detected in both rice bran and wheat fermented by A. tamarii. Some of the identified metabolites have the potential to be applied in the pharmaceutical industry. In conclusion, our study emphasizes A. tamarii’s efficacy in diverse metabolite production under optimized conditions, providing valuable insights for maximizing fungal metabolite production in potential pharmaceutical applications.

Recommendations on data sharing in HIV drug resistance research.

• Human immunodeficiency virus (HIV) drug resistance has implications for antiretroviral treatment strategies and for containing the HIV pandemic because the development of HIV drug resistance leads to the requirement for antiretroviral drugs that may be less effective, less well-tolerated, and more expensive than those used in first-line regimens. • HIV drug resistance studies are designed to determine which HIV mutations are selected by antiretroviral drugs and, in turn, how these mutations affect antiretroviral drug susceptibility and response to future antiretroviral treatment regimens. • Such studies collectively form a vital knowledge base essential for monitoring global HIV drug resistance trends, interpreting HIV genotypic tests, and updating HIV treatment guidelines. • Although HIV drug resistance data are collected in many studies, such data are often not publicly shared, prompting the need to recommend best practices to encourage and standardize HIV drug resistance data sharing. • In contrast to other viruses, sharing HIV sequences from phylogenetic studies of transmission dynamics requires additional precautions as HIV transmission is criminalized in many countries and regions. • Our recommendations are designed to ensure that the data that contribute to HIV drug resistance knowledge will be available without undue hardship to those publishing HIV drug resistance studies and without risk to people living with HIV.

Removal of lansoprazole one of the most prescribed drugs in Turkey from an aqueous solution by innovative magnetic nanomaterial Tween 85®PEI@Fe3O4

It is known that global drug resistance is increasing challenge at an alarming rate worldwide. Lansoprazole (LPZ) is one of Turkey's most prescribed anti-ulcer drugs to treat acid-related disorders. Turkey is the country with the highest drug resistance among OECD countries. This paper presents a study on LPZ's adsorption evaluation from aquatic media using a modified Iron Oxide (Fe3O4), which was synthesized with Polyethyleneimine (PEI) and Polyoxymethylene Sorbitan Trioleate (Tween 85). The removal efficiency of the PEI@Fe3O4®Tween-85 reached 96 % within 30 min. at pH 8. Even with 0.2 g adsorbent, >90 % LPZ removal was achieved. Significant removal of LPZ was observed after 1 min. Contact time. This process indicates that the LPZ adsorption is physical and demonstrates a thermodynamic behavior of an exothermic reaction. Pseudo-second order kinetics revealed a reasonable regression value (>0.99) that the model is best fitted. The Freundlich isotherm model well described equilibrium adsorption data. The maximum adsorption capacity of Lansoprazole was 131.06 mg/g by the magnetite composite adsorbent. Experimental results demonstrate that this adsorbent possessed the advantages of superior adsorptive to the PEI surface, rapid synthesis, and pore diameters in the range of 70–100 nm (nanoscale) after hydrophobic modification.

Recent Advancement of Colorectal Cancer and Their Herbal Essential Oil Treatment

Colorectal cancer is the second most deadly type of cancer (CRC). In the upcoming decades, death and incidence rates would surely increase globally. Despite being disproportionately high in high-income countries, CRC-related mortality is also on the rise in low- and middle-income countries. Early diagnosis of CRC allows for both surgical and medicinal treatment options. Due to the high likelihood of recurrence and the rising rate of treatment failure brought on by cancer medicine resistance, it is regrettable that there is a significant treatment failure rate. Due to early discovery and treatment of CRC, there is a chance of survival in wealthy nations. Contrarily, these resources are noticeably scarce in less developed countries. It is crucial to inform the public about CRC's current situation, its cause, progression, risk factors, and therapy. As a result, we have included in this review all of the most recent data on the global epidemiology, drug resistance, challenges, risk factors, and preventative and therapeutic approaches for CRC. Guidelines for CRC prevention and therapy are briefly reviewed, as well as pathways of CRC developments.

Establishment and application of a method of tagged-amplicon deep sequencing for low-abundance drug resistance in HIV-1

In the latest HIV-1 global drug resistance report released by WHO, countries are advised to strengthen pre-treatment monitoring of drug resistance in AIDS patients. In this study, we established an NGS-based segmented amplification HIV-1 drug resistance mutation detection method. The pol region of HIV-1 was divided into three short fragments for NGS. The entire amplification and sequencing panel were more cost-effective and batched by using the barcode sequence corresponding to the sample. Each parameter was evaluated using samples with known resistance variants frequencies. The nucleotide sequence error rate, amino acid error rate, and noise value of the NGS-based segmented amplification method were both less than 1%. When the threshold was 2%, the consensus sequences of the HIV-1 NL4-3 strain were completely consistent with the Sanger sequences. This method can detect the minimum viral load of the sample at 102 copies/ml, and the input frequency and detection frequency of HIV-1 resistance mutations within the range of 1%–100% had good conformity (R2 = 0.9963; R2 = 0.9955). This method had no non-specific amplification for Hepatitis B and C. Under the 2% threshold, the incidence of surveillance drug resistance mutations in ART-naive HIV-infected patients was 20.69%, among which NRTIs class resistance mutations were mainly.

AgNPs Targeting the Drug Resistance Problem of Staphylococcus aureus: Susceptibility to Antibiotics and Efflux Effect.

The present work presents translational research with application of AgNPs targeting the global drug resistance problem. In vivo fieldwork was carried out with 400 breeding farm cows sick with a serous mastitis. Ex vivo results revealed that after cow treatment with LactobayTM (a mixture of antibiotic drugs) the susceptibility to 31 antibiotics of S. aureus isolates from cow breast secretion decreased by 25%, while after treatment with Argovit–CTM silver nanoparticles S. aureus susceptibility increased by 11%. The portion of isolates with an efflux effect leading to elimination of antibiotics from S. aureus after Lactobay-treatment resulted in a 15% increase, while Argovit-C-treatment led to a 17.5% decrease. The obtained results showed that mastitis treatments with Argovit-CTM AgNPs can partially restore the activity of antibiotics towards S. aureus and shorten the duration of mastitis treatment by 33%.

Colorectal Cancer: A Review of Carcinogenesis, Global Epidemiology, Current Challenges, Risk Factors, Preventive and Treatment Strategies.

Simple SummaryThe high lethality of colorectal cancer (CRC) is anticipated to continue in the following decades. Early-stage CRC is entirely treatable with surgery and adjuvant therapy (chemotherapy/radiotherapy). However, recurrence is common, and cancer drug resistance increases the chances of treatment failure. At the same time, there are many risk factors leading to high prevalence among both genders. Despite significant improvements in treating other cancers, CRC management is not yet at a satisfactory level. In this comprehensive review, we discussed the development of CRC and its associated risk factors, preventive and treatment strategies and proposed some recommendations. Furthermore, besides chemotherapy and targeted therapy, we discussed natural products as therapeutics for CRC.Colorectal cancer (CRC) is the second most deadly cancer. Global incidence and mortality are likely to be increased in the coming decades. Although the deaths associated with CRC are very high in high-income countries, the incidence and fatalities related to CRC are growing in developing countries too. CRC detected early is entirely curable by surgery and subsequent medications. However, the recurrence rate is high, and cancer drug resistance increases the treatment failure rate. Access to early diagnosis and treatment of CRC for survival is somewhat possible in developed countries. However, these facilities are rarely available in developing countries. Highlighting the current status of CRC, its development, risk factors, and management is crucial in creating public awareness. Therefore, in this review, we have comprehensively discussed the current global epidemiology, drug resistance, challenges, risk factors, and preventive and treatment strategies of CRC. Additionally, there is a brief discussion on the CRC development pathways and recommendations for preventing and treating CRC.

Complete Genome Sequence of an Antimicrobial-Producing Bacillus velezensis Sam8H1 Isolate from the Makgadikgadi Saltpans of Botswana

The global antimicrobial drug resistance crisis requires urgency in searching for more effective broad-spectrum antimicrobial drugs. Here, we present a complete circular genome sequence and a plasmid of an antimicrobial-producing isolate, Bacillus velezensis strain Sam8H1, from the Makgadikgadi saltpans in Botswana. Bioinformatic analyses revealed 12 putative secondary metabolite biosynthetic gene clusters important for genome-guided drug discovery studies.

The versatility of carbohydrates in antimicrobial applications

AbstractThe worsening situation of global drug resistance is urgently demanding for novel antimicrobial agents. Considerable efforts have been concentrated on developing new antibacterial therapies with new mode of actions, exerting no selective pressure on bacterial mutation, and minimizing toxicity to host cells. In this context, active targeting can greatly contribute to selectivity between pathogens and mammalian cells in which carbohydrates, playing important roles in numerous biological processes, can be employed as targeting ligands or “trojan horse.” This short account has discussed the recent results of carbohydrate‐based antimicrobial agents developed by our group. Other excellent works by other scientists and possible directions in the future are also discussed.

Structural Basis for the Inhibition of Mycobacterial MmpL3 by NITD-349 and SPIRO

Novel antitubercular agents are urgently needed to combat the emergence of global drug resistance to human tuberculosis. Mycobacterial membrane protein Large 3 (MmpL3) is a promising drug target because its activity is essential and required for cell-wall biosynthesis. Several classes of MmpL3 inhibitors have been developed against Mycobacterium tuberculosis (Mtb) with potent anti-tuberculosis activity. These include the drug candidate SQ109, which has progressed to phase IIb/III clinical trials. Here, we have determined the crystal structures of MmpL3 in complex with NITD-349 and SPIRO. Both inhibitors bind deep in the central channel of transmembrane domain and cause conformational changes to the protein. The amide nitrogen and indole nitrogen of NITD-349 and the piperidine nitrogen of SPIRO interact and clamp Asp645. Structural analysis of the two structures reveals that these inhibitors target the proton relay pathway to block the activity of MmpL3. The findings presented here enrich our understanding of the binding modes of MmpL3 inhibitors and provide directions to enable further rational drug design targeting MmpL3.

Biofunctions of antimicrobial peptide-conjugated alginate/hyaluronic acid/collagen wound dressings promote wound healing of a mixed-bacteria-infected wound

The increase in severe infections caused by antibiotic drug resistance and the decrease in the number of new antibacterial drugs approved for use in the last few decades are driving the need for the development of new antimicrobial strategies. Antimicrobial peptides (AMPs) are a potential new class of antimicrobial drugs that are expected to solve the problem of global antibiotic drug resistance. Herein, the AMP Tet213 was immobilised onto the substrates of alginate (ALG), hyaluronic acid (HA), and collagen (COL) to form the ALG/HA/COL-AMP wound dressing. This wound dressing exhibited a high degree of swelling and the appropriate porosity, mechanical properties, and biodegradability. The Tet213-immobilised ALG/HA/COL dressings exhibited antimicrobial activity against three pathogenic bacterial strains (Gram-negative E. coli and Gram-positive MRSA and S. aureus) and facilitated the proliferation of NIH 3T3 fibroblast cells. In addition, the ALG/HA/COL-AMP antimicrobial dressings promoted wound healing, re-epithelialisation, collagen deposition, and angiogenesis. Moreover, the wound-healing effects of ALG/HA/COL-AMP surpassed the gauze and ALG/HA/COL compared to commercially available silver-based dressings (Aguacel Ag). These results suggest that the Tet213-conjugated ALG/HA/COL wound dressing, with its multiple biological activities, is a promising wound-dressing material.

A new Mycobacterium leprae dihydropteroate synthase variant (V39I) from Papua, Indonesia

Indonesia had the third highest number of new leprosy cases worldwide in 2017. This disease is still prevalent in Papua province, where the number of new cases in 2014 (3.0 cases per 10,000 people) is considered highly endemic and is well above the World Health Organization's (WHO) cutoff of <1 new case per 10,000 people. Since 1995, the WHO has supplied Papua province with a multi-drug therapy (MDT) in which multibacillary (MB) patients are treated with rifampicin, clofazimine, and dapsone and paucibacillary (PB) patients are treated with rifampicin and dapsone. Recent published data on global drug resistance reported cases of dapsone resistance in relapsed and newly diagnosed cases in Indonesia during this period. The detection of specific point mutations in folP1 that encode dihydropteroate synthases (DHPS) is used exclusively to identify dapsone resistant strains of Mycobacterium leprae. The purpose of this study was to test for the presence of folP1 mutations in M. leprae strains isolated from patients residing in Papua Island, Indonesia who responded less effectively to dapsone. This study identified a folP1 point mutation that changed a valine (V) residue at amino acid position 39 (from the N-terminus) to isoleucine (I) (V39I) of DHPS. The V39I variant is located within an α-helix motif that may not much affect its structure. Molecular docking analysis indicated that the binding affinity of the V39I variant was slightly reduced as compared to the wildtype of DHPS. The decreasing of affinity may have a consequence of increasing inhibition constants (Ki) of dapsone on the variant V39I of DHPS. The data suggest that the DHPS V39I variant might cause less sensitive to dapsone. However, in vivo studies (e.g., mouse footpad model) are needed to confirm the effect of this DHPS variant on dapsone therapy.

Role of circulating tumor cell spheroids in drug resistance.

Cancer cell spheroids are used for drug screening as these three-dimensional (3D) assemblies recapitulate tumors more realistic than the widely employed 2D in vitro cultures. Limited drug diffusion and gradients of oxygen and nutrients in spheroids represent avascular tumor regions containing quiescent and hypoxic tumor cells with high drug resistance. Circulating tumor cells (CTCs) effect metastatic spread and are present in high numbers in malignant diseases such as small-cell lung cancer (SCLC) and in other cancer patients with high tumor load. CTCs are heterogeneous and only a small fraction of these cells survive in the circulation and cause distal lesions. CTCs may circulate as single cells but small CTC clusters or CTC spheroids have been detected in cancer patients and demonstrated to possess increased metastatic potential. At our lab we have obtained 9 permanent SCLC CTC cell lines (BHGc7, BHGc10, BHGc16, BHGc26, BHGc27, BHGc50, BHGc59, BHGc71, and UHGc5) of distinct patients exhibiting similar characteristics and spontaneous formation of large spheroids, termed tumorospheres. These aggregates were shown to exhibit high drug resistance compared to the corresponding single cell suspensions. The increased metastatic capability of small circulating tumor clusters/spheroids may be explained by their role as putative precursors of tumorospheres eventually trapped in capillaries. Limited drug penetration and the presence of hypoxic/quiescent cells can readily account for the global drug resistance of advanced SCLC which has resulted in clinical failure of a wide range of chemotherapeutics and low survival. Furthermore, we have detected such tumorospheres in non-small-cell lung cancer (NSCLC) patients progressing under EGFR-directed tyrosine kinase inhibitor therapy which had undergone NSCLC-SCLC transformation.

Progress in global drug resistance patterns and drug resistance mechanisms of Mycoplasma pneumoniae

Mycoplasma pneumoniae (M.pneumoniae) is one of the predominant pathogenic bacteria causing community acquired pneumonia. An epidemic of M. pneumoniae infection occurs every three to seven years worldwide. It can cause a variety of clinical symptoms. Since 2000, macrolide-resistant M. pneumoniae strains have become increasingly common in many countries around the world and the drug resistance rate has reached as high as 100% in some area, which has posed a great threat to human health. This paper will review the status and mechanism of drug resistance in M. pneumoniae. Key words: Mycoplasma pneumoniae; Global drug resistance; Drug resistance mechanism

A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance

BackgroundTuberculosis (TB) is a major global health problem and drug resistance compromises the efforts to control this disease. Pyrazinamide (PZA) is an important drug used in both first and second line treatment regimes. However, its complete mechanism of action and resistance remains unclear.ResultsWe genotyped and sequenced the complete genomes of 68 M. tuberculosis strains isolated from unrelated TB patients in Peru. No clustering pattern of the strains was verified based on spoligotyping. We analyzed the association between PZA resistance with non-synonymous mutations and specific genes.We found mutations in pncA and novel genes significantly associated with PZA resistance in strains without pncA mutations. These included genes related to transportation of metal ions, pH regulation and immune system evasion.ConclusionsThese results suggest potential alternate mechanisms of PZA resistance that have not been found in other populations, supporting that the antibacterial activity of PZA may hit multiple targets.

Genetic Characterization of a Panel of Diverse HIV-1 Isolates at Seven International Sites.

HIV-1 subtypes and drug resistance are routinely tested by many international surveillance groups. However, results from different sites often vary. A systematic comparison of results from multiple sites is needed to determine whether a standardized protocol is required for consistent and accurate data analysis. A panel of well-characterized HIV-1 isolates (N = 50) from the External Quality Assurance Program Oversight Laboratory (EQAPOL) was assembled for evaluation at seven international sites. This virus panel included seven subtypes, six circulating recombinant forms (CRFs), nine unique recombinant forms (URFs) and three group O viruses. Seven viruses contained 10 major drug resistance mutations (DRMs). HIV-1 isolates were prepared at a concentration of 107 copies/ml and compiled into blinded panels. Subtypes and DRMs were determined with partial or full pol gene sequences by conventional Sanger sequencing and/or Next Generation Sequencing (NGS). Subtype and DRM results were reported and decoded for comparison with full-length genome sequences generated by EQAPOL. The partial pol gene was amplified by RT-PCR and sequenced for 89.4%-100% of group M viruses at six sites. Subtyping results of majority of the viruses (83%-97.9%) were correctly determined for the partial pol sequences. All 10 major DRMs in seven isolates were detected at these six sites. The complete pol gene sequence was also obtained by NGS at one site. However, this method missed six group M viruses and sequences contained host chromosome fragments. Three group O viruses were only characterized with additional group O-specific RT-PCR primers employed by one site. These results indicate that PCR protocols and subtyping tools should be standardized to efficiently amplify diverse viruses and more consistently assign virus genotypes, which is critical for accurate global subtype and drug resistance surveillance. Targeted NGS analysis of partial pol sequences can serve as an alternative approach, especially for detection of low-abundance DRMs.