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1.
Pharmacol Res ; 185: 106477, 2022 11.
Article in English | MEDLINE | ID: covidwho-2049743

ABSTRACT

Receptor expression-enhancing proteins (REEPs) are an evolutionarily conserved protein family that is pivotal to the structure and function of the endoplasmic reticulum (ER). The REEP family can be classified into two major subfamilies in higher species, the REEP1-4 and REEP5-6 subfamilies. Within the REEP1-4 subfamily, REEP1 and REEP2 are closely related, and REEP3 and REEP4 are similarly related. The REEP family is widely distributed in various tissues. Recent studies indicate that the REEP family is involved in many pathological and physiological processes, such as ER morphogenesis and remodeling, microtubule cytoskeleton regulation, and the trafficking and expression of G protein-coupled receptors (GPCRs). Moreover, the REEP family plays crucial roles in the occurrence and development of many diseases, including neurological diseases, diabetes, retinal diseases, cardiac diseases, infertility, obesity, oligoarticular juvenile idiopathic arthritis (OJIA), COVID-19, and cancer. In the present review, we describe the distribution and structure of the REEP family. Furthermore, we summarize the functions and the associated diseases of this family. Based on the pleiotropic actions of the REEP family, the study of its family members is crucial to understanding the relevant pathophysiological processes and developing strategies to modulate and control these related diseases.


Subject(s)
COVID-19 , Humans , Endoplasmic Reticulum/metabolism , Carrier Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , Cytoskeleton/metabolism , Membrane Transport Proteins/metabolism
2.
Epigenomics ; 14(3): 153-162, 2022 02.
Article in English | MEDLINE | ID: covidwho-1622527

ABSTRACT

Smoking could predispose individuals to a more severe COVID-19 by upregulating a particular gene known as mdig, which is mediated through a number of well-known histone modifications. Smoking might regulate the transcription-activating H3K4me3 mark, along with the transcription-repressing H3K9me3 and H3K27me3 marks, in a way to favor SARS-CoV-2 entry by enhancing the expression of ACE2, NRP1 and NRP2, AT1R, CTSD and CTSL, PGE2 receptors 2-4, SLC6A20 and IL-6, all of which interact either directly or indirectly with important receptors, facilitating viral entry in COVID-19.


Lay abstract The role of smoking in development of several respiratory diseases has been clearly established. A significant proportion of these deleterious effects is mediated through epigenetic mechanisms, particularly histone modifications. Recent evidence indicates that smoking induces the expression of a mediator known as mdig, which in turn alters the transcription of several key proteins that have been implicated in development of COVID-19.


Subject(s)
COVID-19/genetics , Dioxygenases/genetics , Epigenesis, Genetic , Histone Demethylases/genetics , Histones/genetics , Nuclear Proteins/genetics , Protein Processing, Post-Translational , Smoking/genetics , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/diagnosis , COVID-19/metabolism , COVID-19/virology , Cathepsin D/genetics , Cathepsin D/metabolism , Cathepsin L/genetics , Cathepsin L/metabolism , Dioxygenases/metabolism , Histone Demethylases/metabolism , Histones/metabolism , Humans , Interleukin-6/genetics , Interleukin-6/metabolism , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Methylation , Neuropilin-1/genetics , Neuropilin-1/metabolism , Neuropilin-2/genetics , Neuropilin-2/metabolism , Nuclear Proteins/metabolism , Protein Isoforms/genetics , Protein Isoforms/metabolism , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Receptors, Prostaglandin E/genetics , Receptors, Prostaglandin E/metabolism , Risk Factors , SARS-CoV-2/genetics , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Smoking/metabolism , Smoking/pathology , Virus Internalization
3.
Cells ; 11(1)2021 12 24.
Article in English | MEDLINE | ID: covidwho-1580995

ABSTRACT

The lamellar body (LB) of the alveolar type II (ATII) cell is a lysosome-related organelle (LRO) that contains surfactant, a complex mix of mainly lipids and specific surfactant proteins. The major function of surfactant in the lung is the reduction of surface tension and stabilization of alveoli during respiration. Its lack or deficiency may cause various forms of respiratory distress syndrome (RDS). Surfactant is also part of the innate immune system in the lung, defending the organism against air-borne pathogens. The limiting (organelle) membrane that encloses the LB contains various transporters that are in part responsible for translocating lipids and other organic material into the LB. On the other hand, this membrane contains ion transporters and channels that maintain a specific internal ion composition including the acidic pH of about 5. Furthermore, P2X4 receptors, ligand gated ion channels of the danger signal ATP, are expressed in the limiting LB membrane. They play a role in boosting surfactant secretion and fluid clearance. In this review, we discuss the functions of these transporting pathways of the LB, including possible roles in disease and as therapeutic targets, including viral infections such as SARS-CoV-2.


Subject(s)
COVID-19/metabolism , Ion Channels/metabolism , Lung/metabolism , Membrane Transport Proteins/metabolism , Pulmonary Surfactants/metabolism , COVID-19/virology , Humans , Lung/virology , Organelles/metabolism , Organelles/virology , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/virology , SARS-CoV-2/physiology
4.
Elife ; 102021 12 06.
Article in English | MEDLINE | ID: covidwho-1555530

ABSTRACT

Background: Lipid metabolism plays an important role in viral infections. We aimed to assess the causal effect of lipid-lowering drugs (HMGCR inhibitiors, PCSK9 inhibitiors, and NPC1L1 inhibitior) on COVID-19 outcomes using two-sample Mendelian randomization (MR) study. Methods: We used two kinds of genetic instruments to proxy the exposure of lipid-lowering drugs, including expression quantitative trait loci of drugs target genes, and genetic variants within or nearby drugs target genes associated with low-density lipoprotein (LDL cholesterol from genome-wide association study). Summary-data-based MR (SMR) and inverse-variance-weighted MR (IVW-MR) were used to calculate the effect estimates. Results: SMR analysis found that a higher expression of HMGCR was associated with a higher risk of COVID-19 hospitalization (odds ratio [OR] = 1.38, 95% confidence interval [CI] = 1.06-1.81). Similarly, IVW-MR analysis observed a positive association between HMGCR-mediated LDL cholesterol and COVID-19 hospitalization (OR = 1.32, 95% CI = 1.00-1.74). No consistent evidence from both analyses was found for other associations. Conclusions: This two-sample MR study suggested a potential causal relationship between HMGCR inhibition and the reduced risk of COVID-19 hospitalization. Funding: Start-up Fund for high-level talents of Fujian Medical University.


The virus SARS-CoV-2 has caused millions of infections and deaths during the COVID-19 pandemic, but as of December 2021, no new drugs targeted to SARS-CoV-2 specifically exist. Thus, it is important to identify existing drugs that can reduce the infection and mortality of this virus, since repurposing old drugs is faster and cheaper than developing new ones. Fats, such as cholesterol, can play an important role in viral infections, meaning that drugs intended to lower the levels of fats in the blood could have a protective effect against SARS-CoV-2. To test this hypothesis, Huang, Xiao, et al. carried out a Mendelian randomization study to investigate if there is a link between drugs that lower fats and outcomes of SARS-CoV-2 infection, including susceptibility, hospitalization, and severe disease. This approach consists on grouping people according to their version of a particular gene, which minimizes the effect of variables that can cause spurious associations, something known as confounding bias. Thus, Mendelian randomization studies allow scientists to disentangle cause and effect. Using this method, Huang, Xiao, et al. found an association between statins (a type of drug that decreases the levels of bad cholesterol) and a reduced risk of being hospitalized after being infected with SARS-CoV-2. These findings suggest that statins could benefit patients infected with SARS-CoV-2, and indicate that they should be prioritized in future clinical trials for treating COVID-19.


Subject(s)
COVID-19/drug therapy , Hypolipidemic Agents/pharmacology , Antiviral Agents/pharmacology , Humans , Hydroxymethylglutaryl CoA Reductases/metabolism , Membrane Transport Proteins/metabolism , Mendelian Randomization Analysis , Proprotein Convertase 9/metabolism , Treatment Outcome
5.
Xenobiotica ; 52(2): 152-164, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1541325

ABSTRACT

Emvododstat was identified as a potent inhibitor of dihydroorotate dehydrogenase and is now in clinical development for the treatment of acute myeloid leukaemia and COVID-19. The objective of this paper is to evaluate the metabolism, pharmacokinetics, and drug interaction potentials of emvododstat.Emvododstat showed high binding to plasma protein with minimal distribution into blood cells in mouse, rat, dog, monkey, and human whole blood.O-Demethylation followed by glucuronidation appeared to be the major metabolic pathway in rat, dog, monkey, and human hepatocytes. CYP2C8, 2C19, 2D6, and 3A4 were involved in O-desmethyl emvododstat metabolite formation. Both emvododstat and O-desmethyl emvododstat inhibited CYP2D6 activity and induced CYP expression to different extents in vitro.Emvododstat and O-desmethyl emvododstat inhibited BCRP transporter activity but did not inhibit bile salt transporters and other efflux or uptake transporters. Neither emvododstat nor O-desmethyl emvododstat was a substrate for common efflux or uptake transporters investigated.Emvododstat is bioavailable in mice, rats, dogs, and monkeys following a single oral dose. The absorption was generally slow with the mean plasma Tmax ranging from 2 to 5 h; plasma exposure of O-desmethyl emvododstat was lower in rodents, but relatively higher in dogs and monkeys.


Subject(s)
COVID-19 , Microsomes, Liver , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Animals , Carbamates , Carbazoles , Dogs , Drug Interactions , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Membrane Transport Proteins/metabolism , Mice , Microsomes, Liver/metabolism , Neoplasm Proteins/metabolism , Rats
6.
Physiol Rep ; 9(21): e15061, 2021 11.
Article in English | MEDLINE | ID: covidwho-1513250

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) and transmembrane proteases (TMPRSS) are multifunctional proteins required for SARS-CoV-2 infection or for amino acid (AA) transport, and are abundantly expressed in mammalian small intestine, but the identity of the intestinal cell type(s) and sites of expression are unclear. Here we determined expression of SARS-CoV-2 entry factors in different cell types and then compared it to that of representative AA, electrolyte, and mineral transporters. We tested the hypothesis that SARS-CoV-2, AA, electrolyte, and mineral transporters are expressed heterogeneously in different intestinal cell types by making mouse enteroids enriched in enterocytes (ENT), goblet (GOB), Paneth (PAN), or stem (ISC) cells. Interestingly, the expression of ACE2 was apical and modestly greater in ENT, the same pattern observed for its associated AA transporters B0 AT1 and SIT1. TMPRSS2 and TMPRSS4 were more highly expressed in crypt-residing ISC. Expression of electrolyte transporters was dramatically heterogeneous. DRA, NBCe1, and NHE3 were greatest in ENT, while those of CFTR and NKCC1 that play important roles in secretory diarrhea, were mainly expressed in ISC and PAN that also displayed immunohistochemically abundant basolateral NKCC1. Intestinal iron transporters were generally expressed higher in ENT and GOB, while calcium transporters were expressed mainly in PAN. Heterogeneous expression of its entry factors suggests that the ability of SARS-CoV-2 to infect the intestine may vary with cell type. Parallel cell-type expression patterns of ACE2 with B0 AT1 and SIT1 provides further evidence of ACE2's multifunctional properties and importance in AA absorption.


Subject(s)
COVID-19/virology , Electrolytes/metabolism , Epithelial Cells/metabolism , Intestines/physiology , Membrane Transport Proteins/metabolism , Minerals/metabolism , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/metabolism , COVID-19/pathology , COVID-19/transmission , Epithelial Cells/cytology , Epithelial Cells/virology , Immunohistochemistry , Intestines/cytology , Intestines/virology , Male , Membrane Proteins/metabolism , Mice , SARS-CoV-2/isolation & purification , Serine Endopeptidases/metabolism
7.
Clin Pharmacol Ther ; 110(1): 108-122, 2021 07.
Article in English | MEDLINE | ID: covidwho-1212738

ABSTRACT

Numerous drugs are currently under accelerated clinical investigation for the treatment of coronavirus disease 2019 (COVID-19); however, well-established safety and efficacy data for these drugs are limited. The goal of this study was to predict the potential of 25 small molecule drugs in clinical trials for COVID-19 to cause clinically relevant drug-drug interactions (DDIs), which could lead to potential adverse drug reactions (ADRs) with the use of concomitant medications. We focused on 11 transporters, which are targets for DDIs. In vitro potency studies in membrane vesicles or HEK293 cells expressing the transporters coupled with DDI risk assessment methods revealed that 20 of the 25 drugs met the criteria from regulatory authorities to trigger consideration of a DDI clinical trial. Analyses of real-world data from electronic health records, including a database representing nearly 120,000 patients with COVID-19, were consistent with several of the drugs causing transporter-mediated DDIs (e.g., sildenafil, chloroquine, and hydroxychloroquine). This study suggests that patients with COVID-19, who are often older and on various concomitant medications, should be carefully monitored for ADRs. Future clinical studies are needed to determine whether the drugs that are predicted to inhibit transporters at clinically relevant concentrations, actually result in DDIs.


Subject(s)
Antiviral Agents , COVID-19 , Drug Interactions , Drug-Related Side Effects and Adverse Reactions , Membrane Transport Proteins/metabolism , Virus Internalization/drug effects , Virus Replication/drug effects , Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , COVID-19/virology , Clinical Trials as Topic , Drug Monitoring/methods , Drug Monitoring/standards , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/metabolism , Drug-Related Side Effects and Adverse Reactions/prevention & control , Electronic Health Records/statistics & numerical data , HEK293 Cells , Humans , Hydroxychloroquine/pharmacokinetics , Risk Assessment/methods , SARS-CoV-2/drug effects , SARS-CoV-2/physiology
9.
J Exp Med ; 218(4)2021 04 05.
Article in English | MEDLINE | ID: covidwho-1061104

ABSTRACT

Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here we have isolated primary SARS-CoV-2 viral strains and studied their interaction with human plasmacytoid predendritic cells (pDCs), a key player in antiviral immunity. We show that pDCs are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus-induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2-induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2-induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN-dependent immunity against SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , COVID-19/metabolism , Cell Plasticity/immunology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Interleukin-1 Receptor-Associated Kinases/metabolism , Membrane Transport Proteins/metabolism , SARS-CoV-2/immunology , Biomarkers , COVID-19/drug therapy , COVID-19/virology , Cytokines/metabolism , Dendritic Cells/virology , Host-Pathogen Interactions/immunology , Humans , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Immunomodulation , Immunophenotyping , Inflammation Mediators/metabolism , Interferon Type I/metabolism , Interferons/metabolism
11.
Elife ; 92020 11 09.
Article in English | MEDLINE | ID: covidwho-969888

ABSTRACT

Respiratory failure associated with COVID-19 has placed focus on the lungs. Here, we present single-nucleus accessible chromatin profiles of 90,980 nuclei and matched single-nucleus transcriptomes of 46,500 nuclei in non-diseased lungs from donors of ~30 weeks gestation,~3 years and ~30 years. We mapped candidate cis-regulatory elements (cCREs) and linked them to putative target genes. We identified distal cCREs with age-increased activity linked to SARS-CoV-2 host entry gene TMPRSS2 in alveolar type 2 cells, which had immune regulatory signatures and harbored variants associated with respiratory traits. At the 3p21.31 COVID-19 risk locus, a candidate variant overlapped a distal cCRE linked to SLC6A20, a gene expressed in alveolar cells and with known functional association with the SARS-CoV-2 receptor ACE2. Our findings provide insight into regulatory logic underlying genes implicated in COVID-19 in individual lung cell types across age. More broadly, these datasets will facilitate interpretation of risk loci for lung diseases.


Subject(s)
COVID-19/genetics , COVID-19/virology , Host Microbial Interactions/genetics , Lung/metabolism , Lung/virology , Adult , Age Factors , Alveolar Epithelial Cells/classification , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Child, Preschool , Chromosome Mapping , Gene Expression Profiling , Genetic Variation , Host Microbial Interactions/physiology , Humans , Infant, Newborn , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Pandemics , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Single-Cell Analysis , Virus Internalization
12.
Curr Drug Metab ; 21(14): 1127-1135, 2020.
Article in English | MEDLINE | ID: covidwho-968953

ABSTRACT

BACKGROUND: In clinical practice, chloroquine and hydroxychloroquine are often co-administered with other drugs in the treatment of malaria, chronic inflammatory diseases, and COVID-19. Therefore, their metabolic properties and the effects on the activity of cytochrome P450 (P450, CYP) enzymes and drug transporters should be considered when developing the most efficient treatments for patients. METHODS: Scientific literature on the interactions of chloroquine and hydroxychloroquine with human P450 enzymes and drug transporters, was searched using PUBMED.Gov (https://pubmed.ncbi.nlm.nih.gov/) and the ADME database (https://life-science.kyushu.fujitsu.com/admedb/). RESULTS: Chloroquine and hydroxychloroquine are metabolized by P450 1A2, 2C8, 2C19, 2D6, and 3A4/5 in vitro and by P450s 2C8 and 3A4/5 in vivo by N-deethylation. Chloroquine effectively inhibited P450 2D6 in vitro; however, in vivo inhibition was not apparent except in individuals with limited P450 2D6 activity. Chloroquine is both an inhibitor and inducer of the transporter MRP1 and is also a substrate of the Mate and MRP1 transport systems. Hydroxychloroquine also inhibited P450 2D6 and the transporter OATP1A2. CONCLUSIONS: Chloroquine caused a statistically significant decrease in P450 2D6 activity in vitro and in vivo, also inhibiting its own metabolism by the enzyme. The inhibition indicates a potential for clinical drug-drug interactions when taken with other drugs that are predominant substrates of the P450 2D6. When chloroquine and hydroxychloroquine are used clinically with other drugs, substrates of P450 2D6 enzyme, attention should be given to substrate-specific metabolism by P450 2D6 alleles present in individuals taking the drugs.


Subject(s)
Chloroquine/metabolism , Cytochrome P-450 Enzyme Inhibitors/metabolism , Cytochrome P-450 Enzyme System/metabolism , Hydroxychloroquine/metabolism , Membrane Transport Proteins/metabolism , Animals , COVID-19/drug therapy , COVID-19/metabolism , Chloroquine/therapeutic use , Cytochrome P-450 Enzyme Inhibitors/therapeutic use , Drug Interactions/physiology , Humans , Hydroxychloroquine/therapeutic use , Pharmaceutical Preparations/metabolism
13.
Clin Sci (Lond) ; 134(21): 2823-2833, 2020 11 13.
Article in English | MEDLINE | ID: covidwho-899996

ABSTRACT

ACE2 is a type I membrane protein with extracellular carboxypeptidase activity displaying a broad tissue distribution with highest expression levels at the brush border membrane (BBM) of small intestine enterocytes and a lower expression in stomach and colon. In small intestinal mucosa, ACE2 mRNA expression appears to increase with age and to display higher levels in patients taking ACE-inhibitors (ACE-I). There, ACE2 protein heterodimerizes with the neutral amino acid transporter Broad neutral Amino acid Transporter 1 (B0AT1) (SLC6A19) or the imino acid transporter Sodium-dependent Imino Transporter 1 (SIT1) (SLC6A20), associations that are required for the surface expression of these transport proteins. These heterodimers can form quaternary structures able to function as binding sites for SARS-CoV-2 spike glycoproteins. The heterodimerization of the carboxypeptidase ACE2 with B0AT1 is suggested to favor the direct supply of substrate amino acids to the transporter, but whether this association impacts the ability of ACE2 to mediate viral infection is not known. B0AT1 mutations cause Hartnup disorder, a condition characterized by neutral aminoaciduria and, in some cases, pellagra-like symptoms, such as photosensitive rash, diarrhea, and cerebellar ataxia. Correspondingly, the lack of ACE2 and the concurrent absence of B0AT1 expression in small intestine causes a decrease in l-tryptophan absorption, niacin deficiency, decreased intestinal antimicrobial peptide production, and increased susceptibility to inflammatory bowel disease (IBD) in mice. Thus, the abundant expression of ACE2 in small intestine and its association with amino acid transporters appears to play a crucial role for the digestion of peptides and the absorption of amino acids and, thereby, for the maintenance of structural and functional gut integrity.


Subject(s)
Amino Acid Transport Systems, Neutral/metabolism , Betacoronavirus/pathogenicity , Coronavirus Infections/enzymology , Intestinal Absorption , Intestinal Mucosa/enzymology , Membrane Transport Proteins/metabolism , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/enzymology , Virus Internalization , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Coronavirus Infections/virology , Host-Pathogen Interactions , Humans , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/metabolism , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/virology , Protein Multimerization , SARS-CoV-2
14.
Int J Mol Sci ; 21(17)2020 Aug 27.
Article in English | MEDLINE | ID: covidwho-831264

ABSTRACT

Outside of Mycobacterium tuberculosis and Mycobacterium leprae, nontuberculous mycobacteria (NTM) are environmental mycobacteria (>190 species) and are classified as slow- or rapid-growing mycobacteria. Infections caused by NTM show an increased incidence in immunocompromised patients and patients with underlying structural lung disease. The true global prevalence of NTM infections remains unknown because many countries do not require mandatory reporting of the infection. This is coupled with a challenging diagnosis and identification of the species. Current therapies for treatment of NTM infections require multidrug regimens for a minimum of 18 months and are associated with serious adverse reactions, infection relapse, and high reinfection rates, necessitating discovery of novel antimycobacterial agents. Robust drug discovery processes have discovered inhibitors targeting mycobacterial membrane protein large 3 (MmpL3), a protein responsible for translocating mycolic acids from the inner membrane to periplasm in the biosynthesis of the mycobacterial cell membrane. This review focuses on promising new chemical scaffolds that inhibit MmpL3 function and represent interesting and promising putative drug candidates for the treatment of NTM infections. Additionally, agents (FS-1, SMARt-420, C10) that promote reversion of drug resistance are also reviewed.


Subject(s)
Anti-Bacterial Agents/pharmacology , Membrane Transport Proteins/metabolism , Mycobacterium Infections, Nontuberculous/drug therapy , Nontuberculous Mycobacteria/metabolism , Anti-Bacterial Agents/therapeutic use , Bacterial Proteins/metabolism , Biological Transport/drug effects , Drug Discovery , Drug Resistance, Multiple, Bacterial/drug effects , Gene Expression Regulation, Bacterial/drug effects , Humans , Iodophors/pharmacology , Iodophors/therapeutic use , Isoxazoles/pharmacology , Isoxazoles/therapeutic use , Mycobacterium Infections, Nontuberculous/metabolism , Mycolic Acids/metabolism , Nontuberculous Mycobacteria/drug effects , Polysaccharides/pharmacology , Polysaccharides/therapeutic use , Spiro Compounds/pharmacology , Spiro Compounds/therapeutic use
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