Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections

2013 ◽  
Author(s):  
Andrew M. Gulick ◽  
Thomas A. Russo ◽  
L. W. Schultz ◽  
Timothy C. Umland
Keyword(s):  
Drug Targets ◽  
Bacterial Infections ◽  
Drug Resistant ◽  
New Drug

scholarly journals Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections

2014 ◽  
Author(s):  
Andrew M. Gulick ◽  
Thomas A. Russo ◽  
L. W. Schulz ◽  
Timothy C. Umland
Keyword(s):  
Drug Targets ◽  
Bacterial Infections ◽  
Drug Resistant ◽  
New Drug

scholarly journals Identification of a Novel Therapeutic Target against XDR Salmonella Typhi H58 Using Genomics Driven Approach Followed Up by Natural Products Virtual Screening

2021 ◽  
Vol 9 (12) ◽  
pp. 2512
Author(s):  
Khurshid Jalal ◽  
Kanwal Khan ◽  
Muhammad Hassam ◽  
Muhammad Naseer Abbas ◽  
Reaz Uddin ◽  
...  
Keyword(s):  
Typhoid Fever ◽  
Drug Targets ◽  
Salmonella Typhi ◽  
Drug Resistant ◽  
Acid Biosynthesis ◽  
New Drug ◽  
Subtractive Genomics ◽  
Colanic Acid ◽  
Novel Drug ◽  
Potential Drug Targets

Typhoid fever is caused by a pathogenic, rod-shaped, flagellated, and Gram-negative bacterium known as Salmonella Typhi. It features a polysaccharide capsule that acts as a virulence factor and deceives the host immune system by protecting phagocytosis. Typhoid fever remains a major health concern in low and middle-income countries, with an estimated death rate of ~200,000 per annum. However, the situation is exacerbated by the emergence of the extensively drug-resistant (XDR) strain designated as H58 of S. Typhi. The emergence of the XDR strain is alarming, and it poses serious threats to public health due to the failure of the current therapeutic regimen. A relatively newer computational method called subtractive genomics analyses has been widely applied to discover novel and new drug targets against pathogens, particularly drug-resistant ones. The method involves the gradual reduction of the complete proteome of the pathogen, leading to few potential and novel drug targets. Thus, in the current study, a subtractive genomics approach was applied against the Salmonella XDR strain to identify potential drug targets. The current study predicted four prioritized proteins (i.e., Colanic acid biosynthesis acetyltransferase wcaB, Shikimate dehydrogenase aroE, multidrug efflux RND transporter permease subunit MdtC, and pantothenate synthetase panC) as potential drug targets. Though few of the prioritized proteins are treated in the literature as the established drug targets against other pathogenic bacteria, these drug targets are identified here for the first time against S. Typhi (i.e., S. Typhi XDR). The current study aimed at drawing attention to new drug targets against S. Typhi that remain largely unexplored. One of the prioritized drug targets, i.e., Colanic acid biosynthesis acetyltransferase, was predicted as a unique, new drug target against S. Typhi XDR. Therefore, the Colanic acid was further explored using structure-based techniques. Additionally, ~1000 natural compounds were docked with Colanic acid biosynthesis acetyltransferase, resulting in the prediction of seven compounds as potential lead candidates against the S. Typhi XDR strain. The ADMET properties and binding energies via the docking program of these seven compounds characterized them as novel drug candidates. They may potentially be used for the development of future drugs in the treatment of Typhoid fever.

Discovery of Alzheimer's Molecular Pathway Reveals New Drug Targets

ASHA Leader ◽  
2013 ◽  
Vol 18 (3) ◽  
pp. 33-33
Keyword(s):  
Drug Targets ◽  
Molecular Pathway ◽  
New Drug

Discovery of Alzheimer's Molecular Pathway Reveals New Drug Targets

Mycobacterial DNA Replication as a Target for Antituberculosis Drug Discovery

2017 ◽  
Vol 17 (19) ◽  
pp. 2129-2142 ◽  
Author(s):  
Renata Płocinska ◽  
Malgorzata Korycka-Machala ◽  
Przemyslaw Plocinski ◽  
Jaroslaw Dziadek
Keyword(s):  
Drug Resistance ◽  
Dna Replication ◽  
Drug Targets ◽  
Rapid Development ◽  
New Drugs ◽  
Drug Resistant ◽  
Antituberculosis Drug ◽  
Nucleotide Synthesis ◽  
Antituberculosis Therapy ◽  
Optimal Drug

Background: Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, is a leading infectious disease organism, causing millions of deaths each year. This serious pathogen has been greatly spread worldwide and recent years have observed an increase in the number of multi-drug resistant and totally drug resistant M. tuberculosis strains (WHO report, 2014). The danger of tuberculosis becoming an incurable disease has emphasized the need for the discovery of a new generation of antimicrobial agents. The development of novel alternative medical strategies, new drugs and the search for optimal drug targets are top priority areas of tuberculosis research. Factors: Key characteristics of mycobacteria include: slow growth, the ability to transform into a metabolically silent - latent state, intrinsic drug resistance and the relatively rapid development of acquired drug resistance. These factors make finding an ideal antituberculosis drug enormously challenging, even if it is designed to treat drug sensitive tuberculosis strains. A vast majority of canonical antibiotics including antituberculosis agents target bacterial cell wall biosynthesis or DNA/RNA processing. Novel therapeutic approaches are being tested to target mycobacterial cell division, twocomponent regulatory factors, lipid synthesis and the transition between the latent and actively growing states. Discussion and Conclusion: This review discusses the choice of cellular targets for an antituberculosis therapy, describes putative drug targets evaluated in the recent literature and summarizes potential candidates under clinical and pre-clinical development. We focus on the key cellular process of DNA replication, as a prominent target for future antituberculosis therapy. We describe two main pathways: the biosynthesis of nucleic acids precursors – the nucleotides, and the synthesis of DNA molecules. We summarize data regarding replication associated proteins that are critical for nucleotide synthesis, initiation, unwinding and elongation of the DNA during the replication process. They are pivotal processes required for successful multiplication of the bacterial cells and hence they are extensively investigated for the development of antituberculosis drugs. Finally, we summarize the most potent inhibitors of DNA synthesis and provide an up to date report on their status in the clinical trials.

Re-challenging antibiotic resistance with Daniel Berman

2020 ◽  
Author(s):  
Daniel Berman
Keyword(s):  
Bacterial Infections ◽  
Point Of Care ◽  
Healthcare Setting ◽  
Rapid Diagnostic Tests ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Drug Resistant Bacteria ◽  
Global Threat ◽  
The Right ◽  
Point Of Care Tests

How can we prevent the rise of resistance to antibiotics? In this video, Daniel Berman,  Nesta Challenges, discusses the global threat of AMR and how prizes like the Longitude Prize can foster the development of rapid diagnostic tests for bacterial infections, helping to contribute towards reducing the global threat of drug resistant bacteria. Daniel outlines how accelerating the development of rapid point-of-care tests will ensure that bacterial infections are treated with the most appropriate antibiotic, at the right time and in the right healthcare setting.

scholarly journals Intrinsically Disordered Proteins as Regulators of Transient Biological Processes and as Untapped Drug Targets

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2118
Author(s):  
Yusuke Hosoya ◽  
Junko Ohkanda
Keyword(s):  
Drug Targets ◽  
Intrinsically Disordered Proteins ◽  
Dynamic Control ◽  
Disordered Proteins ◽  
Biological Processes ◽  
Phase Separations ◽  
Cellular Processes ◽  
Intrinsically Disordered ◽  
New Drug ◽  
Liquid Phase Separations

Intrinsically disordered proteins (IDPs) are critical players in the dynamic control of diverse cellular processes, and provide potential new drug targets because their dysregulation is closely related to many diseases. This review focuses on several medicinal studies that have identified low-molecular-weight inhibitors of IDPs. In addition, clinically relevant liquid–liquid phase separations—which critically involve both intermolecular interactions between IDPs and their posttranslational modification—are analyzed to understand the potential of IDPs as new drug targets.

scholarly journals 44. Antibiotic Class-Based Distribution and Analysis of Reported Beta-Lactam Allergies amongst Hospitalized Patients

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S45-S45
Author(s):  
Joseph Patrik Hornak ◽  
David Reynoso
Keyword(s):  
Bacterial Infections ◽  
Drug Resistant ◽  
Beta Lactam ◽  
Resistance Development ◽  
Texas Medical ◽  
University Of Texas ◽  
Icd 10 ◽  
Mrsa Infection ◽  
The University ◽  
Alternative Antibiotic

Abstract Background Reported β-lactam allergy (BLA) is very common, yet less than 10% of these patients exhibit true hypersensitivity. When faced with reported BLAs, physicians often choose alternative antibiotics which can be associated with C. difficile infection, drug-resistance development, poorer outcomes, & increased costs. Effective identification of these patients is necessary for subsequent, appropriate BLA “de-labeling.” Here, we conducted a single-center analysis of alternative antibiotic utilization amongst patients reporting BLA and compare the frequency of drug-resistant infections and C. difficile infection in allergic & non-allergic patients. Methods This is a retrospective review of adult patients hospitalized at The University of Texas Medical Branch from 1/1/2015 to 12/31/2019. Pooled electronic medical records were filtered by antibiotic orders and reported allergies to penicillins or cephalosporins. Patients with drug-resistant and/or C. difficile infection (CDI) were identified by ICD-10 codes. Microsoft Excel & MedCalc were used for statistical calculations. Results Data were available for 118,326 patients and 9.3% (11,982) reported a BLA, with the highest rates seen in those receiving aztreonam (85.9%, 530/617) & clindamycin (33.7%, 3949/11718). Amongst patients reporting BLA, high ratios-of-consumption (relative to all patients receiving antibiotics) were seen with aztreonam (7.0), clindamycin (2.7), cephalosporin/β-lactamase inhibitors (2.4), & daptomycin (2.1). Compared to the non-BLA population, BLA patients more frequently experienced MRSA infection (3.0% vs 1.5%, OR 1.99, 95% CI 1.79–2.23, p< 0.0001), β-lactam resistance (1.2% vs 0.6%, OR 2.07, 95% CI 1.72–2.49, p< 0.0001), and CDI (1.2% vs 0.7%, OR 1.85, 95% CI 1.54–2.23, p< 0.0001). Conclusion Our measured BLA rate matches approximate expectations near 10%. Moreover, these patients experienced significantly higher frequencies of drug-resistant bacterial infections and CDI. Targeted inpatient penicillin allergy testing stands to be particularly effective in those patients receiving disproportionately utilized alternative agents (e.g. aztreonam, clindamycin, daptomycin). β-lactam allergy “de-labeling” in these patients is likely a valuable antimicrobial stewardship target. Disclosures All Authors: No reported disclosures

scholarly journals Label-Free Comparative Proteomics of Differentially Expressed Mycobacterium tuberculosis Protein in Rifampicin-Related Drug-Resistant Strains

Pathogens ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 607
Author(s):  
Nadeem Ullah ◽  
Ling Hao ◽  
Jo-Lewis Banga Ndzouboukou ◽  
Shiyun Chen ◽  
Yaqi Wu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Control Strategies ◽  
Multidrug Resistant ◽  
Differentially Expressed ◽  
Effective Control ◽  
Drug Resistant ◽  
Differentially Expressed Proteins ◽  
Label Free ◽  
Candidate Target

Rifampicin (RIF) is one of the most important first-line anti-tuberculosis (TB) drugs, and more than 90% of RIF-resistant (RR) Mycobacterium tuberculosis clinical isolates belong to multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. In order to identify specific candidate target proteins as diagnostic markers or drug targets, differential protein expression between drug-sensitive (DS) and drug-resistant (DR) strains remains to be investigated. In the present study, a label-free, quantitative proteomics technique was performed to compare the proteome of DS, RR, MDR, and XDR clinical strains. We found iniC, Rv2141c, folB, and Rv2561 were up-regulated in both RR and MDR strains, while fadE9, espB, espL, esxK, and Rv3175 were down-regulated in the three DR strains when compared to the DS strain. In addition, lprF, mce2R, mce2B, and Rv2627c were specifically expressed in the three DR strains, and 41 proteins were not detected in the DS strain. Functional category showed that these differentially expressed proteins were mainly involved in the cell wall and cell processes. When compared to the RR strain, Rv2272, smtB, lpqB, icd1, and folK were up-regulated, while esxK, PPE19, Rv1534, rpmI, ureA, tpx, mpt64, frr, Rv3678c, esxB, esxA, and espL were down-regulated in both MDR and XDR strains. Additionally, nrp, PPE3, mntH, Rv1188, Rv1473, nadB, PPE36, and sseA were specifically expressed in both MDR and XDR strains, whereas 292 proteins were not identified when compared to the RR strain. When compared between MDR and XDR strains, 52 proteins were up-regulated, while 45 proteins were down-regulated in the XDR strain. 316 proteins were especially expressed in the XDR strain, while 92 proteins were especially detected in the MDR strain. Protein interaction networks further revealed the mechanism of their involvement in virulence and drug resistance. Therefore, these differentially expressed proteins are of great significance for exploring effective control strategies of DR-TB.

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