The Spectrum of Thiazolidinediones against Respiratory Tract Pathogenic Bacteria: An In Vitro and In Silico Approach

2020 ◽  
Vol 21 (14) ◽  
pp. 1457-1469
Author(s):  
Mohammed Al Bratty ◽  
Ayman Q. Hakami ◽  
Hatim A. Masmali ◽  
Md. Shamsher Alam ◽  
Hassan A. Alhazmi ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Broad Spectrum ◽  
In Silico ◽  
Respiratory Tract Infections ◽  
Binding Proteins ◽  
Bacterial Resistance ◽  
Penicillin Binding Proteins ◽  
Minimum Inhibitory Concentrations ◽  
Tract Infections

Background and Objectives: Drug design strategies to develop novel broad-spectrum antibacterial agents for the treatment of respiratory tract infections that can combat bacterial resistance are currently gaining momentum. 2,4-thiazolidinedione is a structural scaffold that contains pharmacophores similar to β-lactam and non- β-lactam antibiotics. The objective of the study was to synthesize newer 3,5-Disubstituted-2,4-Thiazolidinediones (DTZDs) and subject them to in vitro antibacterial screening against bacterial pathogens. Also, we performed in silico docking of selected compounds to penicillin-binding proteins and beta-lactamases. Methods: Intermediate Schiff bases were prepared by the reaction between 2,4-thiazolidinedione and an appropriate aldehyde followed by acylation of the ring nitrogen with 3-brompropanoyl chloride resulting in DTZDs. Minimum inhibitory concentrations were determined against few bacteria infecting the respiratory tract by the broth tube dilution method. Zones of inhibitions against the bacteria were also determined using agar well diffusion technique. Molecular docking of the compounds to all types of Penicillin-Binding Proteins (PBPs) and β-lactamases was also carried out. Results: Compounds DTZD12 and DTZD16 exhibited broad-spectrum antibacterial activity. The minimum inhibitory concentrations of the compounds were 175μg/100μL. Measurements of the zones of inhibitions indicated that compound DTZD12 was more active than DZTD16. E. coli was the most susceptible organism. Docking results established that both the compounds were able to interact with PBPs and β-lactamases through strong hydrogen bonds, especially the unique interaction with active serine residue of the PBP for inhibition of cell wall synthesis. Conclusion: DTZD12 and DTZD16 can be developed into antibacterial drugs for respiratory tract infections to oppose bacterial resistance, or can also be used as leads for repurposing the existing 2,4- thiazolidinediones.

Telithromycin: The First of the Ketolides

2002 ◽  
Vol 36 (3) ◽  
pp. 452-464 ◽  
Author(s):  
Christopher S Shain ◽  
Guy W Amsden
Keyword(s):  
Respiratory Tract ◽  
Clinical Efficacy ◽  
Respiratory Tract Infections ◽  
Safety Issue ◽  
Qtc Interval ◽  
Phagocytic Cells ◽  
Medline Search ◽  
Atypical Pathogens ◽  
Tract Infections

OBJECTIVE: To review the chemistry, spectrum of activity, pharmacology, clinical efficacy, and safety of telithromycin. DATA SOURCES: A MEDLINE search from 1966 to December 2000 was performed via OVID and PubMed using the following search terms: HMR 3647, HMR3647, Ketek, RU 66647, and telithromycin. An extensive review of retrieved literature, abstracts from international scientific conferences, and minutes from regulatory authority meetings was also performed. DATA EXTRACTION: Medicinal chemistry, in vitro, animal, and human trials were reviewed for information on the antimicrobial activity, clinical efficacy, pharmacology, and safety of telithromycin. DATA SYNTHESIS: Several chemical modifications to the macrolide structure have led to the development of telithromycin, the first ketolide antimicrobial that demonstrates improved activity against penicillin- and macrolide/azalide-resistant Streptococcus pneumoniae due to its unique binding to the ribosomal target site. Although telithromycin may be useful in the treatment of community-acquired respiratory tract infections due to its activity against common typical and atypical pathogens, questions concerning its reliable activity against Haemophilus influenzae need to be addressed. Telithromycin's pharmacokinetics permit once-daily dosing for abbreviated periods and good distribution into lung tissue and phagocytic cells. Clinical and bacteriologic cure rates have been similar to those of comparator agents in human efficacy trials; however, the incidence of adverse gastrointestinal events were generally higher with telithromycin patients. Like other macrolides and many newer fluoroquinolones, telithromycin's ability to prolong the QTc interval is a potential safety issue, especially in elderly patients with predisposing conditions or those who are concurrently receiving drugs that are substrates for CYP2D6 and 3A4. Liver function test elevations demonstrated during clinical trials, although not overtly severe, may warrant monitoring in some patients taking multiple hepatically metabolized/cleared agents. CONCLUSIONS: Telithromycin offers potential advantages over traditional macrolides/azalides for community-acquired respiratory tract infections caused by macrolide-resistant pathogens. Further studies are needed to elucidate its clinical efficacy against H. influenzae, potential drug interactions, and safety in various subpopulations.

scholarly journals Evidence Update for Clinicians: Narrow- versus Broad-Spectrum Antibiotics for Common Infections in Children

2018 ◽  
Author(s):  
Keyword(s):  
Respiratory Tract ◽  
Broad Spectrum ◽  
Respiratory Tract Infections ◽  
Acute Otitis Media ◽  
Streptococcal Pharyngitis ◽  
Upper Respiratory Tract ◽  
Broad Spectrum Antibiotics ◽  
Group A ◽  
Tract Infections ◽  
Common Infections

Comparing Narrow- vs. Broad-Spectrum Antibiotics for Common Infections in Children. The choice of antibiotic to treat acute bacterial upper respiratory tract infections in children can affect both symptom resolution and the risk of side effects such as diarrhea and vomiting. The findings of a PCORI-funded study published in JAMA can help clinicians treating children for acute respiratory tract infections (ARTIs)—including acute otitis media, Group A streptococcal pharyngitis, and acute sinusitis—make decisions with parents about the medicine that is best for the child. The study, led by Jeffrey Gerber, a pediatrician and researcher at the Children’s Hospital of Philadelphia, included 30,086 children ages 6 months to 12 years taking narrow- and broad-spectrum antibiotics to treat ARTIs.

scholarly journals In Vitro Activities of Peptide Deformylase Inhibitors against Gram-Positive Pathogens

2002 ◽  
Vol 46 (4) ◽  
pp. 1117-1118 ◽  
Author(s):  
R. Wise ◽  
J. M. Andrews ◽  
J. Ashby
Keyword(s):  
Respiratory Tract ◽  
Respiratory Tract Infections ◽  
Active Agent ◽  
Peptide Deformylase ◽  
Gram Positive ◽  
Similar Activity ◽  
Amoxicillin Clavulanate ◽  
Tract Infections

ABSTRACT The activities of six peptide deformylase (PDF) inhibitors against 107 respiratory tract pathogens were studied and compared to those of ciprofloxacin and amoxicillin-clavulanate. Against Streptococcus pneumoniae, BB-83698 and BB-83815 were the most active PDF inhibitors (MIC at which 90% of the organisms tested were inhibited [MIC90], 0.25 μg/ml). Five of the agents showed similar activity against Moraxella catarrhalis (MIC90, 0.12 μg/ml). All PDF inhibitors were less active against Haemophilus influenzae; BB-3497 was the most active agent (MIC90, 2 μg/ml). Five agents were studied against Chlamydia spp. and showed activity similar to that of ciprofloxacin (MIC, 0.5 to 4 μg/ml). This study demonstrates that PDF inhibitors have the potential to be developed for the treatment of respiratory tract infections.

scholarly journals In Vitro and Murine Efficacy and Toxicity Studies of Nebulized SCC1, a Methylated Caffeine-Silver(I) Complex, for Treatment of Pulmonary Infections

2009 ◽  
Vol 53 (8) ◽  
pp. 3285-3293 ◽  
Author(s):  
Carolyn L. Cannon ◽  
Lisa A. Hogue ◽  
Ravy K. Vajravelu ◽  
George H. Capps ◽  
Aida Ibricevic ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Respiratory Tract Infections ◽  
Airway Epithelial Cells ◽  
Clinical Strain ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Airway Epithelial ◽  
Tract Infections

ABSTRACT The expanding clinical challenge of respiratory tract infections due to resistant bacteria necessitates the development of new forms of therapy. The development of a compound composed of silver coupled to a methylated caffeine carrier (silver carbene complex 1 [SCC1]) that demonstrated in vitro efficacy against bacteria, including drug-resistant organisms, isolated from patients with respiratory tract infections was described previously. The findings of current in vitro studies now suggest that bactericidal concentrations of SCC1 are not toxic to airway epithelial cells in primary culture. Thus, it was hypothesized that SCC1 could be administered by the aerosolized route to concentrate delivery to the lung while minimizing systemic toxicity. In vivo, aerosolized SCC1 delivered to mice resulted in mild aversion behavior, but it was otherwise well tolerated and did not cause lung inflammation following administration over a 5-day period. The therapeutic efficacy of SCC1 compared to that of water was shown in a 3-day prophylaxis protocol, in which mice infected with a clinical strain of Pseudomonas aeruginosa had increased survival, decreased amounts of bacteria in the lung, and a lower prevalence of bacteremia. Similarly, by using an airway infection model in which bacteria were impacted in the airways by agarose beads, the administration of SCC1 was significantly superior to water in decreasing the lung bacterial burden and the levels of bacteremia and markers of airway inflammation. These observations indicate that aerosolized SCC1, a novel antimicrobial agent, warrants further study as a potential therapy for bacterial respiratory tract infections.

scholarly journals Structure of Macrolide Efflux Protein (MefA/E) in Streptococcus pneumoniae: An in silico approach

2020 ◽  
Author(s):  
Sreeram Chandra Murthy Peela ◽  
Jyoti Sharma ◽  
Sujatha Sistla
Keyword(s):  
Streptococcus Pneumoniae ◽  
Respiratory Tract ◽  
Protein Sequence ◽  
In Silico ◽  
Respiratory Tract Infections ◽  
Major Facilitator Superfamily ◽  
Transmembrane Helices ◽  
E Protein ◽  
Major Facilitator ◽  
Tract Infections

AbstractBackgroundMacrolides are one of the commonest antibiotics used to treat bacterial respiratory tract infections. Resistance to this class of antibiotics is on the rise and is mediated by macrolide efflux (MefA/E) protein as one of the mechanisms. Despite its importance, the structure of this protein is not known yet.MethodsThe publicly available MefA/E protein sequence was used to model the structure. Modelling was performed in I-TASSER, and the model was further refined. Its orientation in a membrane was studied using OPM server.Results and conclusionsThe structure of MefA/E resembled that of Major Facilitator Superfamily (MFS) proteins, with 13 transmembrane helices. It had a V-shaped conformation, with the wider part towards the outer membrane layer.

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