scholarly journals Hydroxylation of Antitubercular Drug Candidate, SQ109, by Mycobacterial Cytochrome P450

2020 ◽  
Vol 21 (20) ◽  
pp. 7683
Author(s):  
Sergey Bukhdruker ◽  
Tatsiana Varaksa ◽  
Irina Grabovec ◽  
Egor Marin ◽  
Polina Shabunya ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Cytochrome P450s ◽  
Drug Candidate ◽  
Antitubercular Drug ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Methyl Group ◽  
Liver Cytochrome ◽  
The One ◽  
Effective Drugs

Spreading of the multidrug-resistant (MDR) strains of the one of the most harmful pathogen Mycobacterium tuberculosis (Mtb) generates the need for new effective drugs. SQ109 showed activity against resistant Mtb and already advanced to Phase II/III clinical trials. Fast SQ109 degradation is attributed to the human liver Cytochrome P450s (CYPs). However, no information is available about interactions of the drug with Mtb CYPs. Here, we show that Mtb CYP124, previously assigned as a methyl-branched lipid monooxygenase, binds and hydroxylates SQ109 in vitro. A 1.25 Å-resolution crystal structure of the CYP124–SQ109 complex unambiguously shows two conformations of the drug, both positioned for hydroxylation of the ω-methyl group in the trans position. The hydroxylated SQ109 presumably forms stabilizing H-bonds with its target, Mycobacterial membrane protein Large 3 (MmpL3). We anticipate that Mtb CYPs could function as analogs of drug-metabolizing human CYPs affecting pharmacokinetics and pharmacodynamics of antitubercular (anti-TB) drugs.

scholarly journals Hydroxylation of antitubercular drug candidate, SQ109, by mycobacterial cytochrome P450

2020 ◽  
Author(s):  
Sergey Bukhdruker ◽  
Tatsiana Varaksa ◽  
Irina Grabovec ◽  
Egor Marin ◽  
Polina Shabunya ◽  
...  
Keyword(s):  
Human Liver ◽  
Multidrug Resistant ◽  
Cytochrome P450s ◽  
Drug Candidate ◽  
Antitubercular Drug ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Methyl Group ◽  
Liver Cytochrome ◽  
Effective Drugs

AbstractSpreading of the multidrug-resistant (MDR) strains of the deadliest pathogen Mycobacterium tuberculosis (Mtb) generates the need for new effective drugs. SQ109 showed activity against resistant Mtb and already advanced to Phase II/III clinical trials. Fast SQ109 degradation is attributed to the human liver Cytochrome P450s (CYPs). However, no information is available about interactions of the drug with Mtb CYPs. Here, we show that Mtb CYP124, previously assigned as a methyl-branched lipid monooxygenase, binds and hydroxylates SQ109 in vitro. A 1.25 Å-resolution crystal structure of the CYP124–SQ109 complex unambiguously shows two conformations of the drug, both positioned for hydroxylation of the ω-methyl group in the trans position. The hydroxylated SQ109 presumably forms stabilizing H-bonds with its target, the Mycobacterial membrane protein Large 3 (MmpL3). We anticipate that Mtb CYPs could function as analogs of drug-metabolizing human CYPs affecting pharmacokinetics and pharmacodynamics of antitubercular (anti-TB) drugs.

scholarly journals In VitroActivity of AZD5847 against Geographically Diverse Clinical Isolates of Mycobacterium tuberculosis

2014 ◽  
Vol 58 (7) ◽  
pp. 4222-4223 ◽  
Author(s):  
Jim Werngren ◽  
Maria Wijkander ◽  
Nasrin Perskvist ◽  
V. Balasubramanian ◽  
Vasan K. Sambandamurthy ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Lavage Fluid ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Cross Resistance ◽  
Drug Candidate ◽  
Content Type ◽  
Geographical Regions ◽  
Lung Biopsies

ABSTRACTThe MIC of the novel antituberculosis (anti-TB) drug AZD5847 was determined against 146 clinical isolates from diverse geographical regions, including eastern Europe, North America, Africa, and Asia, using the automated Bactec Mycobacterial Growth Indicator Tube (MGIT) 960 system. These isolates originated from specimen sources such as sputum, bronchial alveolar lavage fluid, pleural fluid, abscess material, lung biopsies, and feces. The overall MIC90was 1.0 mg/liter (range, 0.125 to 4 mg/liter). The MICs of AZD5847 for isolates ofMycobacterium tuberculosiswere similar among drug-sensitive strains, multidrug-resistant (MDR) strains, and extensively drug resistant (XDR) strains. The goodin vitroactivity of AZD5847 againstM. tuberculosisand the lack of cross-resistance make this agent a promising anti-TB drug candidate.

scholarly journals Curcumin Analogues as a Potential Drug against Antibiotic Resistant Protein, β-Lactamases and L, D-Transpeptidases Involved in Toxin Secretion in Salmonella typhi: A Computational Approach

2021 ◽  
Vol 2 (1) ◽  
pp. 77-100
Author(s):  
Tanzina Akter ◽  
Mahim Chakma ◽  
Afsana Yeasmin Tanzina ◽  
Meheadi Hasan Rumi ◽  
Mst. Sharmin Sultana Shimu ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Typhoid Fever ◽  
Homology Modeling ◽  
Salmonella Typhi ◽  
Multidrug Resistant ◽  
Drug Candidate ◽  
In Vivo Experiments ◽  
Curcumin Analogs

Typhoid fever caused by the bacteria Salmonella typhi gained resistance through multidrug-resistant S. typhi strains. One of the reasons behind β-lactam antibiotic resistance is -lactamase. L, D-Transpeptidases is responsible for typhoid fever as it is involved in toxin release that results in typhoid fever in humans. A molecular modeling study of these targeted proteins was carried out by various methods, such as homology modeling, active site prediction, prediction of disease-causing regions, and by analyzing the potential inhibitory activities of curcumin analogs by targeting these proteins to overcome the antibiotic resistance. The five potent drug candidate compounds were identified to be natural ligands that can inhibit those enzymes compared to controls in our research. The binding affinity of both the Go-Y032 and NSC-43319 were found against β-lactamase was −7.8 Kcal/mol in AutoDock, whereas, in SwissDock, the binding energy was −8.15 and −8.04 Kcal/mol, respectively. On the other hand, the Cyclovalone and NSC-43319 had an equal energy of −7.60 Kcal/mol in AutoDock, whereas −7.90 and −8.01 Kcal/mol in SwissDock against L, D-Transpeptidases. After the identification of proteins, the determination of primary and secondary structures, as well as the gene producing area and homology modeling, was accomplished. The screened drug candidates were further evaluated in ADMET, and pharmacological properties along with positive drug-likeness properties were observed for these ligand molecules. However, further in vitro and in vivo experiments are required to validate these in silico data to develop novel therapeutics against antibiotic resistance.

scholarly journals Anti-Tuberculosis Activity of Extract Ethyl Acetate Kenikir Leaves (Cosmos caudatus H.B.K) and Sendok Leaves (Plantago Major L.) By In Vitro Test

2018 ◽  
Vol 23 (1) ◽  
pp. 1
Author(s):  
Tatang Irianti ◽  
Sylvia Utami Tanjung Pratiwi ◽  
Kuswandi Kuswandi ◽  
Nanan Tresnaasih ◽  
Dharmastuti Cahya ◽  
...  
Keyword(s):  
Ethyl Acetate ◽  
Multidrug Resistant ◽  
Retardation Factor ◽  
Drug Candidate ◽  
In Vitro Test ◽  
Plantago Major ◽  
Cosmos Caudatus ◽  
Lowenstein Jensen ◽  
Ethyl Acetate Extracts

The increasing therapy problem including multidrug-resistant tuberculosis (TB) has made it important to discover a new anti-TB drug candidate. The aim of this study was to acknowledge the activity of ethyl acetate extracts of kenikir (Cosmos caudatus H.B.K) and sendok (Plantago major L.) leaves against Mycobacterium tuberculosis (M. tuberculosis) H37Rv. This research used Middlebrook (MB) 7H9 media and observed the growth of M. tuberculosis using Lowenstein Jensen (LJ) media. The concentration of extracts were 0.25 mg/ml, 0.50 mg/ml, and 1.00 mg/ml. The result of this study showed that ethyl acetate extracts exhibited anti-TB activity in 1000 µg/ml of both extracts. The active compound group was detected by thin layer chromatography (TLC) and the separation of compounds was shown by retardation factor (Rf) and the color of the spots. Based on TLC chromatograms, it is known that there are types of compounds, such as ortho-dihydroxy compounds, phenolic compounds, and compound leads to terpenoids for both extracts.

scholarly journals Pharmacokinetics and target attainment of SQ109 in plasma and human-like tuberculosis lesions in rabbits

2021 ◽  
Author(s):  
Oluwaseun Egbelowo ◽  
Jansy P. Sarathy ◽  
Kamunkhwala Gausi ◽  
Matthew D. Zimmerman ◽  
Han Wang ◽  
...  
Keyword(s):  
Rabbit Model ◽  
Multidrug Resistant ◽  
Clinical Development ◽  
Drug Candidate ◽  
Parameter Estimates ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Bacterial Populations ◽  
Resistant Tuberculosis

SQ109 is a novel well-tolerated drug candidate in clinical development for the treatment of drug resistant tuberculosis (TB). It is the only inhibitor of the MmpL3 mycolic acid transporter in clinical development. No SQ109 resistant mutant has been directly isolated thus far, in vitro, in mice or in patients, tentatively attributed to its multiple targets. It is considered as a potential replacement for poorly tolerated components of multidrug-resistant TB regimens. To prioritize SQ109-containing combinations with best potential for cure and treatment shortening, one must understand its contribution against different bacterial populations in pulmonary lesions. Here we have characterized the pharmacokinetics of SQ109 in the rabbit model of active TB and its penetration at the sites of disease: lung tissue, cellular and necrotic lesions, and caseum. A two-compartment model with first-order absorption and elimination described the plasma pharmacokinetics. At the human-equivalent dose, parameter estimates fell within the ranges published for preclinical species. Tissue concentrations were modelled using an "effect" compartment, showing high accumulation in lung and cellular lesion areas with penetration coefficients in excess of 1,000, and lower passive diffusion in caseum after 7 daily doses. These results, together with the hydrophobic nature and high non-specific caseum binding of SQ109, suggest that multi-week dosing would be required to reach steady state in caseum and poorly vascularized compartments, similar to bedaquiline. Linking lesion pharmacokinetics to SQ109 potency in assays against replicating, non-replicating, and intracellular M. tuberculosis showed SQ109 concentrations markedly above pharmacokinetic-pharmacodynamic targets in lung and cellular lesions throughout the dosing interval. IMPORTANCE Drug-resistant tuberculosis (TB) accounts for over 20% of all fatalities due to drug-resistant pathogens. With recently approved drugs and a promising drug candidate pipeline, the challenge faced by clinical developers is prioritization of drug combinations with the best potential to improve cure rates and shorten treatment duration. To this end, one must understand the contribution of each partner drug against different bacterial populations in pulmonary TB lesions. SQ109 is a safe drug candidate in clinical development for the treatment of multidrug resistant TB. It is active against replicating and non-replicating Mycobacterium tuberculosis persisters in vitro, in mouse models and in patients. SQ109 exhibits extremely low frequency of resistance, unprecedented among all TB drugs so far. Here we characterize the pharmacokinetics and activity of SQ109 at the site of TB disease to inform the selection of drug regimens that account for its lesion-centric pharmacokinetic-pharmacodynamic parameters and best leverage its contribution to efficient disease cure.

scholarly journals 1,4-Azaindole, a Potential Drug Candidate for Treatment of Tuberculosis

2014 ◽  
Vol 58 (9) ◽  
pp. 5325-5331 ◽  
Author(s):  
Monalisa Chatterji ◽  
Radha Shandil ◽  
M. R. Manjunatha ◽  
Suresh Solapure ◽  
Vasanthi Ramachandran ◽  
...  
Keyword(s):  
Antitubercular Activity ◽  
Multidrug Resistant ◽  
Antagonistic Activity ◽  
Drug Candidate ◽  
Content Type ◽  
Human Dose ◽  
Safety Risks ◽  
Infection Models

ABSTRACTNew therapeutic strategies against multidrug-resistant (MDR) and extensively drug-resistant (XDR)Mycobacterium tuberculosisare urgently required to combat the global tuberculosis (TB) threat. Toward this end, we previously reported the identification of 1,4-azaindoles, a promising class of compounds with potent antitubercular activity through noncovalent inhibition of decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1). Further, this series was optimized to improve its physicochemical properties and pharmacokinetics in mice. Here, we describe the short-listing of a potential clinical candidate, compound 2, that has potent cellular activity, drug-like properties, efficacy in mouse and rat chronic TB infection models, and minimalin vitrosafety risks. We also demonstrate that the compounds, including compound 2, have no antagonistic activity with other anti-TB drugs. Moreover, compound 2 shows synergy with PA824 and TMC207in vitro, and the synergy effect is translatedin vivowith TMC207. The series is predicted to have a low clearance in humans, and the predicted human dose for compound 2 is ≤1 g/day. Altogether, our data suggest that a 1,4-azaindole (compound 2) is a promising candidate for the development of a novel anti-TB drug.

scholarly journals Summary and Recommendations from the National Institute of Allergy and Infectious Diseases (NIAID) Workshop “Gonorrhea Vaccines: the Way Forward”

2016 ◽  
Vol 23 (8) ◽  
pp. 656-663 ◽  
Author(s):  
Lee M. Wetzler ◽  
Ian M. Feavers ◽  
Scott D. Gray-Owen ◽  
Ann E. Jerse ◽  
Peter A. Rice ◽  
...  
Keyword(s):  
Infectious Diseases ◽  
Basic Research ◽  
Health Department ◽  
Multidrug Resistant ◽  
Current Status ◽  
Hazard Level ◽  
The One ◽  
The U.S ◽  
The Way

ABSTRACTThere is an urgent need for the development of an antigonococcal vaccine due to the increasing drug resistance found in this pathogen. The U.S. Centers for Disease Control (CDC) have identified multidrug-resistant gonococci (GC) as among 3 “urgent” hazard-level threats to the U.S. population. In light of this, on 29 to 30 June 2015, the National Institute for Allergy and Infectious Diseases (NIAID) sponsored a workshop entitled “Gonorrhea Vaccines: the Way Forward.” The goal of the workshop was to gather leaders in the field to discuss several key questions on the current status of gonorrhea vaccine research and the path forward to a licensed gonorrhea vaccine. Representatives from academia, industry, U.S. Government agencies, and a state health department were in attendance. This review summarizes each of the 4 scientific sessions and a series of 4 breakout sessions that occurred during the one and a half days of the workshop. Topics raised as high priority for future development included (i) reinvigoration of basic research to understand gonococcal infection and immunity to allow intervention in processes essential for infection; (ii) clinical infection studies to establish parallels and distinctions betweenin vitroand animal infection models versus natural human genital and pharyngeal infection and to informin silicomodeling of vaccine impact; and (iii) development of an integrated pipeline for preclinical and early clinical evaluation and direct comparisons of potential vaccine antigens and adjuvants and routes of delivery.

scholarly journals Current status and challenges in drug discovery against the globally important zoonotic cryptosporidiosis

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Guan Zhu ◽  
Jigang Yin ◽  
Gregory D. Cuny
Keyword(s):  
Drug Discovery ◽  
Current Status ◽  
Watery Diarrhea ◽  
Health Concept ◽  
Parasite Biology ◽  
Pass Through ◽  
The One ◽  
Effective Drugs ◽  
Globally Distributed

AbstractThe zoonotic cryptosporidiosis is globally distributed, one of the major diarrheal diseases in humans and animals. Cryptosporidium oocysts are also one of the major environmental concerns, making it a pathogen that fits well into the One Health concept. Despite its importance, fully effective drugs are not yet available. Anti-cryptosporidial drug discovery has historically faced many unusual challenges attributed to unique parasite biology and technical burdens. While significant progresses have been made recently, anti-cryptosporidial drug discovery still faces a major obstacle: identification of systemic drugs that can be absorbed by patients experiencing watery diarrhea and effectively pass through electron-dense (ED) band at the parasite-host cell interface to act on the epicellular parasite. There may be a need to develop an in vitro assay to effectively screen hits/leads for their capability to cross ED band. In the meantime, non-systemic drugs with strong mucoadhesive properties for extended gastrointestinal exposure may represent another direction in developing anti-cryptosporidial therapeutics. For developing both systemic and non-systemic drugs, a non-ruminant animal model exhibiting diarrheal symptoms suitable for routine evaluation of drug absorption and anti-cryptosporidial efficacy may be very helpful.

scholarly journals Antimicrobial Activity of Some Essential Oils against Methicillin-Susceptible and Methicillin-Resistant Staphylococcus pseudintermedius-Associated Pyoderma in Dogs

Animals ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1782 ◽  
Author(s):  
Francesca Paola Nocera ◽  
Simone Mancini ◽  
Basma Najar ◽  
Fabrizio Bertelloni ◽  
Luisa Pistelli ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Essential Oils ◽  
Multidrug Resistant ◽  
Therapeutic Approaches ◽  
Cinnamomum Zeylanicum ◽  
Staphylococcus Pseudintermedius ◽  
Methicillin Resistant ◽  
Resistant Strains ◽  
The One

This study aimed to test in vitro the antimicrobial activity of 11 essential oils (EOs) against four methicillin-resistant Staphylococcus pseudintermedius (MRSP) and four methicillin-susceptible S. pseudintermedius (MSSP) clinical isolates. The obtained findings demonstrated a clear in vitro efficacy of some tested EOs against both MRSP and MSSP strains. Particularly, modal minimum inhibitory concentration (MIC) values ranging from 1:2048 v/v for Melissa officinalis against an MSSP strain to 1:256 v/v for Cymbopogoncitratus against all MRSP strains were observed. The best results, highlighting a modal MIC value of 1:1024 v/v for all tested isolates, was provided by Cinnamomum zeylanicum. Intriguingly, Cinnamomum zeylanicum showed, in many cases, a correspondence between minimum bactericidal concentration (MBC) and MIC values, indicating that the inhibiting dose is also often bactericidal. Moreover, a mild antibacterial and bactericidal activity against both MRSP and MSSP isolates was detected for the other tested EOs. Considering the zoonotic potential of S. pseudintermedius and the increased dissemination of multidrug-resistant strains, the employment of EOs could be useful for the treatment of canine pyoderma. Since antibiotic resistance has become the most urgent issue, from the perspective of the One Health initiative, alternative therapeutic approaches are desirable to limit the use of antibiotics or to improve the efficacy of conventional therapies.

scholarly journals Epidemiology and Treatment of Multidrug-Resistant and Extensively Drug-ResistantPseudomonas aeruginosaInfections

2019 ◽  
Vol 32 (4) ◽  
Author(s):  
Juan P. Horcajada ◽  
Milagro Montero ◽  
Antonio Oliver ◽  
Luisa Sorlí ◽  
Sònia Luque ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Multidrug Resistant ◽  
Therapeutic Window ◽  
Clinical Activity ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Mechanisms Of Resistance ◽  
Content Type ◽  
Extensively Drug Resistant

SUMMARYIn recent years, the worldwide spread of the so-called high-risk clones of multidrug-resistant or extensively drug-resistant (MDR/XDR)Pseudomonas aeruginosahas become a public health threat. This article reviews their mechanisms of resistance, epidemiology, and clinical impact and current and upcoming therapeutic options.In vitroandin vivotreatment studies and pharmacokinetic and pharmacodynamic (PK/PD) models are discussed. Polymyxins are reviewed as an important therapeutic option, outlining dosage, pharmacokinetics and pharmacodynamics, and their clinical efficacy against MDR/XDRP. aeruginosainfections. Their narrow therapeutic window and potential for combination therapy are also discussed. Other “old” antimicrobials, such as certain β-lactams, aminoglycosides, and fosfomycin, are reviewed here. New antipseudomonals, as well as those in the pipeline, are also reviewed. Ceftolozane-tazobactam has clinical activity against a significant percentage of MDR/XDRP. aeruginosastrains, and its microbiological and clinical data, as well as recommendations for improving its use against these bacteria, are described, as are those for ceftazidime-avibactam, which has better activity against MDR/XDRP. aeruginosa, especially strains with certain specific mechanisms of resistance. A section is devoted to reviewing upcoming active drugs such as imipenem-relebactam, cefepime-zidebactam, cefiderocol, and murepavadin. Finally, other therapeutic strategies, such as use of vaccines, antibodies, bacteriocins, anti-quorum sensing, and bacteriophages, are described as future options.

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