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1.
Patient Relat Outcome Meas ; 15: 199-217, 2024.
Article in English | MEDLINE | ID: mdl-38911609

ABSTRACT

Aim: Negative symptoms of schizophrenia (NSS) have been linked with poor functional outcomes. A literature review was performed to identify instruments used to assess functional outcomes and quality of life in clinical trials and observational studies conducted in groups of people with NSS. Methods: Literature search strings were designed using Medical Subject Headings combined with free-text terms and searches were performed using the PubMed, Embase and the Cochrane Library databases. For inclusion, articles were required to be published as full-text articles, in English, over the period 2011-2021, include at least one group or treatment arm of people with NSS and report either functional outcomes or quality of life (QoL). Results: Literature searches identified a total of 3,268 unique hits. After two rounds of screening, 37 publications (covering 35 individual studies) were included in the review. A total of fourteen different instruments were used to assess functional outcomes and eleven different instruments were used to assess QoL. In studies in people with NSS, the most frequently used functional outcome measures were the Personal and Social Performance scale and the Global Assessment of Functioning. The most frequently used QoL instruments included the Manchester Short Assessment of Quality of Life, the Heinrich Carpenter Quality of Life Scale, the Schizophrenia Quality of Life Scale and the EQ-5D. Conclusion: A large number of measures have been used to assess functional outcomes and QoL in people with NSS, these include both generic and condition-specific as well as both interviewer-administered and self-reported instruments.

2.
Front Oncol ; 13: 1160966, 2023.
Article in English | MEDLINE | ID: mdl-37223688

ABSTRACT

Introduction: About half of patients with Acute Myeloid Leukemia (AML) are not eligible for Standard Induction Chemotherapy (SIC). Hypomethylating Agents (HMAs) intravenously (IV) or subcutaneously (SC) in a clinical setting are typically offered as an alternative. However, injectable HMAs may be burdensome for patients given the frequent hospital visits and side effects. This study explored patient treatment preferences for different modes of administration (MOA) and the relative importance of treatment-related characteristics that influence treatment decisions. Methods: Semi-structured 1:1 interviews were conducted with 21 adult patients with AML in Germany, the United Kingdom, and Spain, who are not eligible for SIC, had experience with HMAs or were scheduled to be treated with HMAs. After discussing their experience of living with AML and its treatments, patients were presented with hypothetical treatment scenarios to explore their preferences, and a ranking exercise to assess the relative importance of treatment characteristics that influence their treatment-decisions for AML. Results: Most patients reported an overall preference for oral administration over parenteral routes (71%), mostly due to convenience. Those preferring IV or SC routes (24%) reasoned with faster speed of action and onsite monitoring. When presented with a hypothetical situation of a patient having to choose between two AML treatments that were identical except for their MOA, the majority preferred the oral route (76%). Regarding treatment characteristics that influence treatment decisions, patients most frequently reported efficacy (86%) and side effects (62%) as important, followed by mode of administration (29%), daily life impacts (24%) and location of treatment (hospital versus home) (14%). However, only efficacy and side effects were rated as number one deciding factors (67% and 19%, respectively). Patients most frequently rated dosing regimen (33%) as least important. Conclusion: The insights gained from this study may help support patients with AML who are receiving HMA treatment instead of SIC. A potential oral HMA with similar efficacy and tolerability profiles to injectable HMAs could influence treatment decisions. Furthermore, an oral HMA treatment might decrease the burden of parenteral therapies and improve patients' overall quality of life. However, the extent of influence MOA has on treatment decisions requires further investigation.

4.
ACS Omega ; 6(15): 10288-10305, 2021 Apr 20.
Article in English | MEDLINE | ID: mdl-34056183

ABSTRACT

The nematode Haemonchus contortus (the barber's pole worm) is an endoparasite infecting wild and domesticated ruminants worldwide. Widespread anthelmintic resistance of H. contortus requires alternative strategies to control this parasite. Neuropeptide signaling represents a promising target for anthelmintic drugs. Identification and relative quantification of nematode neuropeptides are, therefore, required for the development of such therapeutic targets. In this work, we undertook the profiling of the whole H. contortus larvae at different stages for the direct sequencing of the neuropeptides expressed at low levels in these tissues. We set out a peptide extraction protocol and a peptidomic workflow to biochemically characterize bioactive peptides from both first-stage (L1) and third-stage larvae (L3) of H. contortus. This work led to the identification and quantification at the peptidomic level of more than 180 mature neuropeptides, including amidated and nonamidated peptides, arising from 55 precursors of H. contortus. The differential peptidomic approach provided evidence that both life stages express most FMRFamide-like peptides (FLPs) and neuropeptide-like proteins (NLPs). The H. contortus peptidome resource, established in this work, could add the discovery of neuropeptide system-targeting drugs for ruminants.

5.
Article in English | MEDLINE | ID: mdl-30858215

ABSTRACT

The most frequent ailment for which antibiotics are prescribed is otitis media (ear infections), which is most commonly caused by Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae Treatment of otitis media is complicated by the fact that the bacteria in the middle ear typically form biofilms, which can be recalcitrant to antibiotic treatment. Furthermore, bacterial respiratory infections can be greatly exacerbated by viral coinfection, which is particularly evidenced by the synergy between influenza and S. pneumoniae In this study, we sought to ascertain the in vivo efficacy of aminomethyl spectinomycin lead 1950, an effective antibacterial agent both in vitro and in vivo against Streptococcus pneumoniae in the context of complex respiratory infections and acute otitis media. A single dose of 1950 significantly reduced bacterial burden in the respiratory tract for all three pathogens, even when species were present in a coinfection model. Additionally, a single dose of 1950 effectively reduced pneumococcal acute otitis media from the middle ear. The agent 1950 also proved efficacious in the context of influenza-pneumococcal super infection. These data further support the development of this family of compounds as potential therapeutic agents against the common causes of complex upper respiratory tract infections and acute otitis media.


Subject(s)
Respiratory Tract Infections/drug therapy , Spectinomycin/therapeutic use , Animals , Female , Haemophilus influenzae/drug effects , Haemophilus influenzae/pathogenicity , Mice , Mice, Inbred BALB C , Moraxella catarrhalis/drug effects , Moraxella catarrhalis/pathogenicity , Otitis Media/drug therapy , Otitis Media/microbiology , Pneumonia/drug therapy , Pneumonia/microbiology , Spectinomycin/administration & dosage , Spectinomycin/chemistry , Streptococcus pneumoniae/drug effects , Streptococcus pneumoniae/pathogenicity
6.
ACS Omega ; 3(12): 18343-18360, 2018 Dec 31.
Article in English | MEDLINE | ID: mdl-30613820

ABSTRACT

A series of novel chalcone and thiol-Michael addition analogues was synthesized and tested against Mycobacterium tuberculosis and other clinically significant bacterial pathogens. Previously reported chalcone-like antibacterials (1a-c and 2) were used as a training set to generate a pharmacophore model. The chalcone derivative hit compound 3 was subsequently identified through a pharmacophore-based virtual screen of the Specs library of >200 000 compounds. Among the newly synthesized chalcones and thiol-Michael addition analogues, chalcones 6r and 6s were active (minimum inhibitory concentrations (MICs) = 1.56-6.25 µg/mL) against Gram-positive pathogens Bacillus anthracis and Staphylococcus aureus [methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA)]. The chalcone thiol-Michael addition derivatives 7j-m showed good to excellent antibacterial activities (MICs = 0.78-6.25 µg/mL) against Enterococcus faecalis, B. anthracis, and S. aureus. Interestingly, the amine-Michael addition analogue 12a showed promising anti-MRSA activity (MIC = 1.56 µg/mL) with a selectivity index of 14 toward mammalian Vero cells. In addition, evaluation of selected compounds against biofilm and planktonic S. aureus (MSSA and MRSA) revealed that 12a exhibited bactericidal activities in these assays, which was overall superior to vancomycin. These properties may result from the compounds dissipating the proton motive force of bacterial membranes.

7.
ACS Infect Dis ; 3(1): 72-88, 2017 01 13.
Article in English | MEDLINE | ID: mdl-28081607

ABSTRACT

Spectinamides are a novel class of antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Their antitubercular activity is derived from both ribosomal affinity and their ability to overcome intrinsic efflux mediated by the Mycobacterium tuberculosis Rv1258c efflux pump. This study explores the structure-activity relationships through analysis of 50 targeted spectinamides. Compounds are evaluated for ribosomal translational inhibition, MIC activity in Rv1258c efflux pump deficient and wild type tuberculosis strains, and efficacy in an acute model of tuberculosis infection. The results of this study show a narrow structure-activity relationship, consistent with a tight ribosome-binding pocket and strict structural requirements to overcome native efflux. Rationalization of ribosomal inhibition data using molecular dynamics simulations showed stable complex formation for halogenated spectinamides consistent with the long post antibiotic effects observed. The lead spectinamides identified in this study demonstrated potent MIC activity against MDR and XDR tuberculosis and had desirable antitubercular class specific features including low protein binding, low microsomal metabolism, no cytotoxicity, and significant reductions in bacterial burdens in the lungs of mice infected with M. tuberculosis. The structure-activity relationships detailed here emphasize the need to examine efflux-mediated resistance in the design of antituberculosis drugs and demonstrate that it is possible to overcome intrinsic efflux with synthetic modification. The ability to understand the structure requirements for this class has produced a variety of new substituted spectinamides, which may provide useful alternative candidates and promote the further development of this class.


Subject(s)
Antitubercular Agents/pharmacology , Ribosomes/drug effects , Spectinomycin/analogs & derivatives , Spectinomycin/pharmacology , Antitubercular Agents/chemistry , Drug Discovery , Models, Molecular , Molecular Structure , Spectinomycin/chemistry , Structure-Activity Relationship
8.
J Antimicrob Chemother ; 72(3): 770-777, 2017 03 01.
Article in English | MEDLINE | ID: mdl-27999020

ABSTRACT

Objectives: New drug regimens employing combinations of existing and experimental antimicrobial agents are needed to shorten treatment of tuberculosis (TB) in humans. The spectinamides are narrow-spectrum semisynthetic analogues of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis . Spectinamides, including lead 1599, have been previously shown to exhibit a promising therapeutic profile in mice as single agents. Here we explore the in vivo activity of lead spectinamides when combined with other agents. Methods: The efficacy of 1599 or 1810 was tested in combination in three increasingly advanced TB mouse models. Mice were infected by aerosol and allowed to establish acute or chronic infection, followed by treatment (≤4 weeks) with the spectinamides alone or in two- and three-drug combination regimens with existing and novel therapeutic agents. Bacteria were enumerated from lungs by plating for cfu. Results: Herein we show the following: (i) 1599 exhibits additive or synergistic activity with most of the first-line agents; (ii) 1599 in combination with rifampicin and pyrazinamide or with bedaquiline and pyrazinamide promotes significantly improved efficacy in the high-dose aerosol model; (iii) 1599 enhances efficacy of rifampicin or pyrazinamide in chronically infected BALB/c mice; and (iv) 1599 is synergistic when administered in combination with rifampicin and pyrazinamide in the C3HeB/FeJ mouse model showing caseous necrotic pulmonary lesions. Conclusions: Spectinamides were effective partner agents for multiple anti-TB agents including bedaquiline, rifampicin and pyrazinamide. None of these in vivo synergistic interactions was predicted from in vitro MIC chequerboard assays. These data support further development of the spectinamides as combination partners with existing and experimental anti-TB agents.


Subject(s)
Antitubercular Agents/therapeutic use , Spectinomycin/chemistry , Spectinomycin/therapeutic use , Tuberculosis/drug therapy , Animals , Disease Models, Animal , Drug Synergism , Drug Therapy, Combination , Lung/drug effects , Lung/microbiology , Mice , Mice, Inbred BALB C , Mycobacterium tuberculosis/drug effects , Pyrazinamide/therapeutic use , Quinolines/therapeutic use , Rifampin/therapeutic use , Tuberculosis/microbiology
9.
J Antibiot (Tokyo) ; 70(1): 65-72, 2017 Jan.
Article in English | MEDLINE | ID: mdl-27189120

ABSTRACT

Exploiting iron-uptake pathways by conjugating ß-lactam antibiotics with iron-chelators, such as catechol and hydroxamic acid is a proven strategy to overcome permeability-related resistance in Gram-negative bacteria. As naturally occurring iron-chelating tetramic acids have not been previously examined for this purpose, an exploratory series of novel ampicillin-tetramic acid hybrids that structurally resemble ureidopenicillins was designed and synthesized. The new analogs were evaluated for the ability to chelate iron and their MIC activities determined against a representative panel of clinically significant bacterial pathogens. The tetramic acid ß-lactam hybrids demonstrated a high affinity to iron in the order of 10-30 M3. The hybrids were less active against Gram-positive bacteria. However, against Gram-negative bacteria, their activity was species dependent with several hybrids displaying improved activity over ampicillin against wild-type Pseudomonas aeruginosa. The anti-Gram-negative activities of the hybrids improved in the presence of clavulanic acid revealing that the tetramic acid moiety did not provide added protection against ß-lactamases. In addition, the hybrids were found to be efflux pump substrates as their activities markedly improved against pump-inactivated strains. Unlike the catechol and hydroxamic acid siderophore ß-lactam conjugates, the activities of the hybrids did not improve under iron-deficient conditions. These results suggest that the tetramic acid hybrids gain permeability via different membrane receptors, or they are outcompeted by native bacterial siderophores with stronger affinities for iron. This study provides a foundation for the further exploitation of the tetramic acid moiety to achieve novel ß-lactam anti-Gram-negative agents, providing that efflux and ß-lactamase mediated resistance is addressed.


Subject(s)
Ampicillin/pharmacology , Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Pyrrolidinones/pharmacology , Ampicillin/administration & dosage , Ampicillin/chemical synthesis , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/chemical synthesis , Drug Design , Drug Resistance, Bacterial , Microbial Sensitivity Tests , Pyrrolidinones/administration & dosage , Pyrrolidinones/chemical synthesis , Siderophores/metabolism , Species Specificity , beta-Lactamases/metabolism , beta-Lactams/administration & dosage , beta-Lactams/chemical synthesis , beta-Lactams/pharmacology
10.
Bioorg Med Chem Lett ; 26(16): 4070-6, 2016 08 15.
Article in English | MEDLINE | ID: mdl-27406794

ABSTRACT

Bacterial infections, caused by Mycobacterium tuberculosis and other problematic bacterial pathogens, continue to pose a significant threat to global public health. As such, new chemotype antibacterial agents are desperately needed to fuel and strengthen the antibacterial drug discovery and development pipeline. As part of our antibacterial research program to develop natural product-inspired new antibacterial agents, here we report synthesis, antibacterial evaluation, and structure-activity relationship studies of an extended chemical library of macrocyclic diarylheptanoids with diverse amine, amide, urea, and sulfonamide functionalities. Results of this study have produced macrocyclic geranylamine and 4-fluorophenethylamine substituted derivatives, exhibiting moderate to good activity against M. tuberculosis and selected Gram-positive bacterial pathogens.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Antitubercular Agents/chemical synthesis , Heptanes/chemistry , Amines/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Gram-Positive Bacteria/drug effects , Heptanes/chemical synthesis , Heptanes/pharmacology , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Structure-Activity Relationship , Sulfonamides/chemistry , Urea/chemistry
11.
J Med Econ ; 19(7): 672-83, 2016 Jul.
Article in English | MEDLINE | ID: mdl-26882484

ABSTRACT

Objective To compare the cost-utility of the glucagon-like peptide-1 receptor agonist albiglutide with those of insulin lispro (both in combination with insulin glargine), insulin glargine, and the dipeptidyl peptidase-4 inhibitor sitagliptin, representing treatments along the type 2 diabetes treatment continuum. Methods The Centre for Outcomes Research and Effectiveness (CORE) Diabetes Model was used for the cost-utility analysis. Data from three Phase 3 clinical trials (HARMONY 6, HARMONY 4, and HARMONY 3) evaluating albiglutide for the treatment of patients with type 2 diabetes were used for the baseline characteristics and treatment effects. Utilities and costs were derived from published sources. Results Albiglutide treatment was associated with an improvement in mean quality-adjusted life expectancy of 0.099, 0.033, and 0.101 years when compared with insulin lispro, insulin glargine, and sitagliptin, respectively. Over the 50-year time horizon, mean total costs in the albiglutide arm were $4332, $2597, and $2223 more than in the other respective treatments. These costs resulted in an incremental cost-utility ratio of $43,541, $79,166, and $22,094 per quality-adjusted life-year (QALY) gained for albiglutide vs insulin lispro, insulin glargine, and sitagliptin, respectively. At a willingness-to-pay threshold of $50,000 per QALY gained, there was a 53.0%, 41.5%, and 67.5% probability of albiglutide being cost-effective compared with the other respective treatments. Limitations This analysis was an extrapolation over a 50-year time horizon based on relatively short-term data obtained during clinical trials. It does not take into account potential differences between the respective treatments in adherence and persistence that can influence both effects and costs. Conclusions Albiglutide represents a reasonable treatment option for patients with type 2 diabetes based on its cost-utility, relative to insulin lispro, insulin glargine, and sitagliptin.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glucagon-Like Peptide 1/analogs & derivatives , Glucagon-Like Peptide 1/agonists , Hypoglycemic Agents/economics , Insulins/economics , Aged , Body Mass Index , Computer Simulation , Cost-Benefit Analysis , Diabetes Complications/economics , Dipeptidyl-Peptidase IV Inhibitors/economics , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Drug Therapy, Combination , Female , Glucagon-Like Peptide 1/economics , Glucagon-Like Peptide 1/therapeutic use , Glycated Hemoglobin/drug effects , Health Status , Humans , Hypoglycemic Agents/therapeutic use , Insulin Glargine/economics , Insulin Glargine/therapeutic use , Insulin Lispro/economics , Insulin Lispro/therapeutic use , Insulins/therapeutic use , Male , Middle Aged , Models, Econometric , Quality-Adjusted Life Years , Sitagliptin Phosphate/economics , Sitagliptin Phosphate/therapeutic use
12.
J Biol Chem ; 291(1): 171-81, 2016 Jan 01.
Article in English | MEDLINE | ID: mdl-26567338

ABSTRACT

Neisseria is a Gram-negative pathogen with phospholipids composed of straight chain saturated and monounsaturated fatty acids, the ability to incorporate exogenous fatty acids, and lipopolysaccharides that are not essential. The FabI inhibitor, AFN-1252, was deployed as a chemical biology tool to determine whether Neisseria can bypass the inhibition of fatty acid synthesis by incorporating exogenous fatty acids. Neisseria encodes a functional FabI that was potently inhibited by AFN-1252. AFN-1252 caused a dose-dependent inhibition of fatty acid synthesis in growing Neisseria, a delayed inhibition of growth phenotype, and minimal inhibition of DNA, RNA, and protein synthesis, showing that its mode of action is through inhibiting fatty acid synthesis. Isotopic fatty acid labeling experiments showed that Neisseria encodes the ability to incorporate exogenous fatty acids into its phospholipids by an acyl-acyl carrier protein-dependent pathway. However, AFN-1252 remained an effective antibacterial when Neisseria were supplemented with exogenous fatty acids. These results demonstrate that extracellular fatty acids are activated by an acyl-acyl carrier protein synthetase (AasN) and validate type II fatty acid synthesis (FabI) as a therapeutic target against Neisseria.


Subject(s)
Acyl Carrier Protein/metabolism , Bacterial Proteins/metabolism , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/antagonists & inhibitors , Fatty Acids/metabolism , Neisseria/enzymology , Bacterial Proteins/isolation & purification , Benzofurans/pharmacology , Coenzyme A Ligases/metabolism , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/isolation & purification , Hydroxamic Acids/pharmacology , Lipopolysaccharides/pharmacology , Models, Biological , Neisseria/drug effects , Neisseria/growth & development , Phospholipids/metabolism , Pyrones/pharmacology , Threonine/analogs & derivatives , Threonine/pharmacology
13.
Bioorg Med Chem Lett ; 26(2): 388-391, 2016 Jan 15.
Article in English | MEDLINE | ID: mdl-26711150

ABSTRACT

Pretomanid (PA-824) is an important nitroimidazole antitubercular agent in late stage clinical trials. However, pretomanid is limited by poor solubility and high protein binding, which presents opportunities for improvement in its physiochemical properties. Conversely, the oxazolidinone linezolid has excellent physicochemical properties and has recently shown impressive activity for the treatment of drug resistant tuberculosis. In this study we explore if incorporation of the outer ring elements found in first and second generation oxazolidinones into the nitroimidazole core of pretomanid can be used to improve its physicochemical and antitubercular properties. The synthesis of pretomanid outer oxazolidinone ring hybrids was successfully performed producing hybrids that maintained antitubercular activity and had improved in vitro physicochemical properties. Three lead compounds were identified and evaluated in a chronic model of tuberculosis infection in mice. However, the compounds lacked efficacy suggesting that portions of PA-824 tail not found in the hybrid molecules are required for in vivo efficacy.


Subject(s)
Antitubercular Agents/therapeutic use , Mycobacterium tuberculosis/drug effects , Nitroimidazoles/therapeutic use , Oxazolidinones/therapeutic use , Tuberculosis/drug therapy , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Chronic Disease , Disease Models, Animal , Mice , Mice, Inbred C57BL , Nitroimidazoles/chemical synthesis , Nitroimidazoles/chemistry , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry
14.
J Antimicrob Chemother ; 71(4): 956-63, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26682963

ABSTRACT

OBJECTIVES: In response to reports of Trypanosoma brucei resistance to the nitroaromatic drug nifurtimox, we evaluated the potential of antituberculosis nitrofuran isoxazolines as inhibitors of trypanosome growth. METHODS: The susceptibility of T. brucei brucei was assessed in vitro. The lowest effective concentration to inhibit growth (EC90) against drug-susceptible and -resistant parasites, time-kill kinetics, reversibility of inhibition and propensity for P-glycoprotein-mediated exclusion from the blood-brain barrier were determined. RESULTS: Nitrofuran isoxazolines were potent inhibitors of T. brucei brucei proliferation at nanomolar concentrations, with pentacyclic nitrofurans being 100-fold more potent than nifurtimox. Activity was sustained against nifurtimox-resistant parasites, suggesting the possibility of a unique mechanism of activation and potential for use in the treatment of drug-resistant infections. Exposure of parasites to the maximum concentrations of Compound 15 achieved in vivo with oral dosing yielded >2 logs of irreversible killing in <4 h, indicating rapid trypanocidal activity. CONCLUSIONS: Pentacyclic nitrofuran isoxazolines warrant further development for the treatment of drug-susceptible and nifurtimox-resistant trypanosome infections.


Subject(s)
Nifurtimox/pharmacology , Nitrofurans/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , ATP Binding Cassette Transporter, Subfamily B/drug effects , ATP Binding Cassette Transporter, Subfamily B/metabolism , Animals , Cell Line , Drug Resistance , Humans , Kinetics , Microbial Sensitivity Tests , Nitrofurans/chemical synthesis , Nitrofurans/toxicity , Trypanocidal Agents/chemical synthesis , Trypanosoma brucei brucei/ultrastructure
15.
Sci Rep ; 5: 13985, 2015 Sep 14.
Article in English | MEDLINE | ID: mdl-26365087

ABSTRACT

Spectinamides are new semi-synthetic spectinomycin derivatives with potent anti-tubercular activity. The reported synergism of the precursor spectinomycin with other antibiotics prompted us to examine whether spectinamides sensitize M. tuberculosis to other antibiotics not traditionally used in the treatment of tuberculosis to potentially expand therapeutic options for MDR/XDR Tuberculosis. Whole cell synergy checkerboard screens were performed using the laboratory strain M. tuberculosis H37Rv, lead spectinamide 1599, and a broad panel of 27 antibiotics. In vitro, 1599 synergized with 11 drugs from 6 antibiotic classes. The observed synergy was tested against clinical isolates confirming synergy with Clarithromycin, Doxycycline and Clindamycin, combinations of which were taken forward for in vivo efficacy determination. Co-administration of 1599 and clarithromycin provided additional bacterial killing in a mouse model of acute tuberculosis infection, but not in a chronic infection model. Further studies indicated that mismatched drug exposure profiles likely permitted induction of phenotypic clarithromycin resistance and subsequent loss of synergism. These studies highlight the importance of validating in vitro synergism and the challenge of matching drug exposures to obtain a synergistic outcome in vivo. Results from this study indicate that a 1599 clarithromycin combination is potentially viable, providing the drug exposures can be carefully monitored.


Subject(s)
Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Acute Disease , Animals , Antitubercular Agents/blood , Antitubercular Agents/therapeutic use , Clarithromycin/blood , Clarithromycin/pharmacology , Clarithromycin/therapeutic use , Clindamycin/blood , Clindamycin/pharmacology , Clindamycin/therapeutic use , Disease Models, Animal , Doxycycline/blood , Doxycycline/pharmacology , Doxycycline/therapeutic use , Drug Resistance, Multiple, Bacterial/drug effects , Drug Synergism , Half-Life , Mice , Microbial Sensitivity Tests , Mycobacterium tuberculosis/isolation & purification , Tuberculosis/drug therapy , Tuberculosis/microbiology
16.
Sci Transl Med ; 7(288): 288ra75, 2015 May 20.
Article in English | MEDLINE | ID: mdl-25995221

ABSTRACT

The antibiotic spectinomycin is a potent inhibitor of bacterial protein synthesis with a unique mechanism of action and an excellent safety index, but it lacks antibacterial activity against most clinically important pathogens. A series of N-benzyl-substituted 3'-(R)-3'-aminomethyl-3'-hydroxy spectinomycins was developed on the basis of a computational analysis of the aminomethyl spectinomycin binding site and structure-guided synthesis. These compounds had ribosomal inhibition values comparable to spectinomycin but showed increased potency against the common respiratory tract pathogens Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, and Moraxella catarrhalis, as well as the sexually transmitted bacteria Neisseria gonorrhoeae and Chlamydia trachomatis. Non-ribosome-binding 3'-(S) isomers of the lead compounds demonstrated weak inhibitory activity in in vitro protein translation assays and poor antibacterial activity, indicating that the antibacterial activity of the series remains on target against the ribosome. Compounds also demonstrated no mammalian cytotoxicity, improved microsomal stability, and favorable pharmacokinetic properties in rats. The lead compound from the series exhibited excellent chemical stability superior to spectinomycin; no interaction with a panel of human receptors and drug metabolism enzymes, suggesting low potential for adverse reactions or drug-drug interactions in vivo; activity in vitro against a panel of penicillin-, macrolide-, and cephalosporin-resistant S. pneumoniae clinical isolates; and the ability to cure mice of fatal pneumococcal pneumonia and sepsis at a dose of 5 mg/kg. Together, these studies indicate that N-benzyl aminomethyl spectinomycins are suitable for further development to treat drug-resistant respiratory tract and sexually transmitted bacterial infections.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Drug Discovery , Drug Resistance, Bacterial , Respiratory Tract Infections/drug therapy , Sexually Transmitted Diseases, Bacterial/drug therapy , Spectinomycin/pharmacology , Animals , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacokinetics , Bacteria/metabolism , Bacteria/pathogenicity , Bacterial Proteins/biosynthesis , Chlorocebus aethiops , Computer Simulation , Computer-Aided Design , Disease Models, Animal , Drug Interactions , Drug Stability , Humans , Male , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Rats , Rats, Sprague-Dawley , Respiratory Tract Infections/diagnosis , Respiratory Tract Infections/microbiology , Ribosomes/drug effects , Ribosomes/metabolism , Sexually Transmitted Diseases, Bacterial/diagnosis , Sexually Transmitted Diseases, Bacterial/microbiology , Spectinomycin/adverse effects , Spectinomycin/analogs & derivatives , Spectinomycin/chemical synthesis , Spectinomycin/pharmacokinetics , Structure-Activity Relationship , Vero Cells
17.
J Med Chem ; 57(20): 8398-420, 2014 Oct 23.
Article in English | MEDLINE | ID: mdl-25238443

ABSTRACT

On the basis of recently reported abyssinone II and olympicin A, a series of chemically modified flavonoid phytochemicals were synthesized and evaluated against Mycobacterium tuberculosis and a panel of Gram-positive and -negative bacterial pathogens. Some of the synthesized compounds exhibited good antibacterial activities against Gram-positive pathogens including methicillin resistant Staphylococcus aureus with minimum inhibitory concentration as low as 0.39 µg/mL. SAR analysis revealed that the 2-hydrophobic substituent and the 4-hydrogen bond donor/acceptor of the 4-chromanone scaffold together with the hydroxy groups at 5- and 7-positions enhanced antibacterial activities; the 2',4'-dihydroxylated A ring and the lipophilic substituted B ring of chalcone derivatives were pharmacophoric elements for antibacterial activities. Mode of action studies performed on selected compounds revealed that they dissipated the bacterial membrane potential, resulting in the inhibition of macromolecular biosynthesis; further studies showed that selected compounds inhibited DNA topoisomerase IV, suggesting complex mechanisms of actions for compounds in this series.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Chalcones/chemistry , Chromones/chemistry , Phloroglucinol/analogs & derivatives , Animals , Anti-Bacterial Agents/chemical synthesis , Chemistry Techniques, Synthetic , Chlorocebus aethiops , DNA Gyrase , DNA Topoisomerase IV/antagonists & inhibitors , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Phloroglucinol/chemistry , Phloroglucinol/pharmacology , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacology , Vero Cells/drug effects
18.
PLoS One ; 9(2): e87909, 2014.
Article in English | MEDLINE | ID: mdl-24505329

ABSTRACT

The reductively activated nitroaromatic class of antimicrobials, which include nitroimidazole and the more metabolically labile nitrofuran antitubercular agents, have demonstrated some potential for development as therapeutics against dormant TB bacilli. In previous studies, the pharmacokinetic properties of nitrofuranyl isoxazolines were improved by incorporation of the outer ring elements of the antitubercular nitroimidazole OPC-67683. This successfully increased stability of the resulting pentacyclic nitrofuran lead compound Lee1106 (referred to herein as 9a). In the current study, we report the synthesis and antimicrobial properties of 9a and panel of 9a analogs, which were developed to increase oral bioavailability. These hybrid nitrofurans remained potent inhibitors of Mycobacterium tuberculosis with favorable selectivity indices (>150) and a narrow spectrum of activity. In vivo, the pentacyclic nitrofuran compounds showed long half-lives and high volumes of distribution. Based on pharmacokinetic testing and lack of toxicity in vivo, 9a remained the series lead. 9a exerted a lengthy post antibiotic effect and was highly active against nonreplicating M. tuberculosis grown under hypoxia. 9a showed a low potential for cross resistance to current antitubercular agents, and a mechanism of activation distinct from pre-clinical tuberculosis candidates PA-824 and OPC-67683. Together these studies show that 9a is a nanomolar inhibitor of actively growing as well as nonreplicating M. tuberculosis.


Subject(s)
Antitubercular Agents , Heterocyclic Compounds, 4 or More Rings , Mycobacterium tuberculosis/metabolism , Nitrofurans , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/pharmacology , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/pharmacology , Nitrofurans/chemical synthesis , Nitrofurans/chemistry , Nitrofurans/pharmacokinetics , Nitrofurans/pharmacology , Tuberculosis/drug therapy
19.
Nat Med ; 20(2): 152-158, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24464186

ABSTRACT

Although the classical antibiotic spectinomycin is a potent bacterial protein synthesis inhibitor, poor antimycobacterial activity limits its clinical application for treating tuberculosis. Using structure-based design, we generated a new semisynthetic series of spectinomycin analogs with selective ribosomal inhibition and excellent narrow-spectrum antitubercular activity. In multiple murine infection models, these spectinamides were well tolerated, significantly reduced lung mycobacterial burden and increased survival. In vitro studies demonstrated a lack of cross resistance with existing tuberculosis therapeutics, activity against multidrug-resistant (MDR) and extensively drug-resistant tuberculosis and an excellent pharmacological profile. Key to their potent antitubercular properties was their structural modification to evade the Rv1258c efflux pump, which is upregulated in MDR strains and is implicated in macrophage-induced drug tolerance. The antitubercular efficacy of spectinamides demonstrates that synthetic modifications to classical antibiotics can overcome the challenge of intrinsic efflux pump-mediated resistance and expands opportunities for target-based tuberculosis drug discovery.


Subject(s)
Amides/pharmacology , Antitubercular Agents/pharmacology , Drug Design , Models, Molecular , Mycobacterium tuberculosis/drug effects , Spectinomycin/pharmacology , Tuberculosis, Multidrug-Resistant/drug therapy , ATP-Binding Cassette Transporters/metabolism , Amides/chemical synthesis , Amides/chemistry , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Bacterial Proteins/metabolism , Drug Resistance, Multiple, Bacterial/drug effects , Mice , Ribosomes/drug effects , Spectinomycin/chemistry , Structure-Activity Relationship
20.
J Diabetes Complications ; 28(1): 10-6, 2014.
Article in English | MEDLINE | ID: mdl-24211091

ABSTRACT

AIMS: To estimate the rate of progression of chronic kidney disease (CKD) among patients with type 2 diabetes (T2D) and calculate medical costs associated with progression. METHODS: We conducted a retrospective cohort study of 25,576 members at Kaiser Permanente who had T2D and at least one serum creatinine measurement in 2005. Using estimated glomerular filtration rate (eGFR), we assigned patients to baseline stages of kidney function (stage 0-2, >60ml/min/1.73m(2), n=21,008; stage 3, 30-59, n=3,885; stage 4, 15-29, n=683). We examined all subsequent eGFRs through 2010 to assess progression of kidney disease. Medical costs at baseline and incremental costs during follow-up were assessed. RESULTS: Mean age of patients was 60.6years, 51% were men, and mean diabetes duration was 5.3years. At baseline, 17.9% of patients with T2D also had stage 3 or 4 CKD. Incremental adjusted costs that occurred over follow-up (from baseline) was on average $4569, $12,617, and $33,162 per patient per year higher among patients who progressed from baseline stage 0-2, stage 3, and stage 4 CKD, respectively, compared to those who did not progress. Across all stages of CKD, those who progressed to a higher stage of CKD from baseline had follow-up costs that ranged from 2 to 4 times higher than those who did not progress. CONCLUSIONS: Progression of CKD in T2D drives substantial medical care costs. Interventions designed to minimize decline in progressive kidney function, particularly among patients with stage 3 or 4 CKD, may reduce the economic burden of CKD in T2D.


Subject(s)
Diabetes Mellitus, Type 2/economics , Renal Insufficiency, Chronic/economics , Aged , Cost of Illness , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Disease Progression , Female , Health Care Costs/trends , Humans , Incidence , Male , Middle Aged , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/etiology , Retrospective Studies , United States/epidemiology
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