Investigation of potential drug targets involved in antibiotic sensing and cell wall modification

The emergence of an increasing number of broad-spectrum antibiotic resistant bacteria such as MRSA over the last decade has made the understanding of the mechanisms underlying resistance critical. Resistance very often involves enzymes associated with the cell wall, a common target of antibiotics. Here we investigate the structure and function of enzymes involved in antibiotic sensing and cell wall modification, while using a customized "cell-free" protein synthesis approach to obtain sufficient yields of promising but difficult-to-express antibacterial drug targets.

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Drilling down in the fight against bacterial superbugs

Science Translational Medicine ◽

10.1126/scitranslmed.aba2901 ◽

2020 ◽

Vol 12 (524) ◽

pp. eaba2901

Author(s):

Megan L. McCain

Keyword(s):

Cell Wall ◽

Resistant Bacteria ◽

Antibiotic Resistant Bacteria ◽

Antibiotic Resistant

Light-activated molecular nanomachines can resensitize antibiotic-resistant bacteria to antibiotics by drilling holes in their cell wall.

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Defeating Antibiotic-Resistant Bacteria: Exploring Alternative Therapies for a Post-Antibiotic Era

International Journal of Molecular Sciences ◽

10.3390/ijms21031061 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1061 ◽

Cited By ~ 11

Author(s):

Chih-Hung Wang ◽

Yi-Hsien Hsieh ◽

Zachary M. Powers ◽

Cheng-Yen Kao

Keyword(s):

Drug Targets ◽

Resistant Bacteria ◽

Combination Therapies ◽

Antibiotic Resistant Bacteria ◽

Antibiotic Resistant ◽

Alternative Drug ◽

Novel Approaches ◽

Antibiotic Discovery ◽

Medical Advances ◽

Common Infections

Antibiotics are one of the greatest medical advances of the 20th century, however, they are quickly becoming useless due to antibiotic resistance that has been augmented by poor antibiotic stewardship and a void in novel antibiotic discovery. Few novel classes of antibiotics have been discovered since 1960, and the pipeline of antibiotics under development is limited. We therefore are heading for a post-antibiotic era in which common infections become untreatable and once again deadly. There is thus an emergent need for both novel classes of antibiotics and novel approaches to treatment, including the repurposing of existing drugs or preclinical compounds and expanded implementation of combination therapies. In this review, we highlight to utilize alternative drug targets/therapies such as combinational therapy, anti-regulator, anti-signal transduction, anti-virulence, anti-toxin, engineered bacteriophages, and microbiome, to defeat antibiotic-resistant bacteria.

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Metagenomic Insights into the Composition and Function of Microbes Associated with the Rootzone of Datura inoxia

BioTech ◽

10.3390/biotech11010001 ◽

2022 ◽

Vol 11 (1) ◽

pp. 1

Author(s):

Savanah Senn ◽

Kelly Pangell ◽

Adrianna L. Bowerman

Keyword(s):

Phenylpropanoid Pathway ◽

Bioactive Molecules ◽

Resistant Bacteria ◽

Antibiotic Resistant ◽

Metabolic Functions ◽

Agricultural Applications ◽

And Function ◽

Next Generation Sequencing Ngs ◽

Functional Analyses ◽

Datura Inoxia

The purpose of this paper is to elucidate the roles that microbes may be playing in the rootzone of the medicinal plant Daturainoxia. We hypothesized that the microbes associated with the Datura rootzone would be significantly different than the similar surrounding fields in composition and function. We also hypothesized that rhizospheric and endophytic microbes would be associated with similar metabolic functions to the plant rootzone they inhabited. The methods employed were microbial barcoding, tests of essential oils against antibiotic resistant bacteria and other soil bacterial isolates, 16S Next Generation Sequencing (NGS) metabarcoding, and Whole Genome Shotgun (WGS) taxonomic and functional analyses. A few of the main bacterial genera of interest that were differentially abundant in the Datura root microbiome were Flavobacterium (p = 0.007), Chitinophaga (p = 0.0007), Pedobacter (p = 6 × 10−5), Bradyhizobium (p = 1 × 10−8), and Paenibacillus (p = 1.46 × 10−6). There was significant evidence that the microbes associated with the Datura rootzone had elevated function related to bacterial chalcone synthase (p = 1.49 × 10−3) and permease genes (p < 0.003). There was some evidence that microbial functions in the Datura rootzone provided precursors to important plant bioactive molecules or were beneficial to plant growth. This is important because these compounds are phyto-protective antioxidants and are precursors to many aromatic bioactive compounds that are relevant to human health. In the context of known interactions, and current results, plants and microbes influence the flavonoid biosynthetic pathways of one other, in terms of the regulation of the phenylpropanoid pathway. This is the first study to focus on the microbial ecology of the Datura rootzone. There are possible biopharmaceutical and agricultural applications of the natural interplay that was discovered during this study of the Datura inoxia rhizosphere.

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Potential Drug Targets in Mycobacterial Cell Wall: Non-Lipid Perspective

Current Drug Discovery Technologies ◽

10.2174/1570163815666180605113609 ◽

2020 ◽

Vol 17 (2) ◽

pp. 147-153

Author(s):

Shrayanee Das ◽

Saif Hameed ◽

Zeeshan Fatima

Keyword(s):

Cell Wall ◽

Drug Targets ◽

Cell Structure ◽

Front Line ◽

New Drug ◽

Mycobacterial Cell ◽

Future Drug ◽

Mycobacterial Cell Wall ◽

Potential Drug Targets ◽

Wall Components

Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB), still remains a deadly disease worldwide. With prolonged usage of anti-TB drugs, the current therapeutic regimes are becoming ineffective, particularly due to emergence of drug resistance in MTB. Under such compelling circumstances, it is pertinent to look for new drug targets. The cell wall envelope of MTB is composed of unique lipids that are frequently targeted for anti-TB therapy. This is evident from the fact that most of the commonly used front line drugs (Isoniazid and Ethambutol) act on lipid machinery of MTB. Thus, despite the fact that much of the attention is towards understanding the MTB lipid biology, in search for identification of new drug targets, our knowledge of bacterial cell wall non-lipid components remains rudimentary and underappreciated. Better understanding of such components of mycobacterial cell structure will help in the identification of new drug targets that can be utilized on the persistent mycobacterium. This review at a common platform summarizes some of the non-lipid cell wall components in MTB that have potential to be exploited as future drug targets.

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A Conserved Machinery Underlies the Synthesis of a Chitosan Layer in the Candida Chlamydospore Cell Wall

mSphere ◽

10.1128/msphere.00080-21 ◽

2021 ◽

Vol 6 (2) ◽

Author(s):

Leo D. Bemena ◽

Kyunghun Min ◽

James B. Konopka ◽

Aaron M. Neiman

Keyword(s):

Cell Wall ◽

Cell Walls ◽

Drug Targets ◽

Therapeutic Strategies ◽

Effective Strategy ◽

Fungal Cell ◽

Detailed Understanding ◽

Cell Wall Assembly ◽

Wall Assembly ◽

Potential Drug Targets

The cell wall is the interface between the fungal cell and its environment and disruption of cell wall assembly is an effective strategy for antifungal therapies. Therefore, a detailed understanding of how cell walls form is critical to identify potential drug targets and develop therapeutic strategies.

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From endolysins to Artilysin®s: novel enzyme-based approaches to kill drug-resistant bacteria

Biochemical Society Transactions ◽

10.1042/bst20150192 ◽

2016 ◽

Vol 44 (1) ◽

pp. 123-128 ◽

Cited By ~ 49

Author(s):

Hans Gerstmans ◽

Lorena Rodríguez-Rubio ◽

Rob Lavigne ◽

Yves Briers

Keyword(s):

Cell Wall ◽

Resistant Bacteria ◽

Infection Cycle ◽

Lytic Enzymes ◽

Gram Positive ◽

Antibiotic Resistant ◽

Gram Negative ◽

Bacterial Agent ◽

Drug Resistant Bacteria ◽

Pass Through

One of the last untapped reservoirs in nature for the identification of new anti-microbials is bacteriophages, the natural killers of bacteria. Lytic bacteriophages encode peptidoglycan (PG) lytic enzymes able to degrade the PG layer in different steps of their infection cycle. Endolysins degrade the bacterial cell wall at the end of the infection cycle, causing lysis of the host to release the viral progeny. Recombinant endolysins have been successfully applied as anti-bacterial agent against antibiotic-resistant Gram-positive pathogens. This has boosted the study of these enzymes as new anti-microbials in different fields (e.g. medical, food technology). A key example is the recent development of endolysin-based anti-bacterials against Gram-negative pathogens in which the exogenous application of endolysins is hindered by the outer membrane (OM). These novel anti-microbials, termed Artilysin®s, are able to pass through the OM and reach the PG where they exert their action. In addition, mycobacteria whose cell wall is structurally different from both Gram-positive and Gram-negative bacteria have also been reported to be inhibited by mycobacteriophage-encoded endolysins. Endolysins and endolysin-based anti-microbials can be considered as ideal candidates for an alternative to antibiotics for several reasons: (1) their unique mode of action and activity against bacterial persisters (independent of an active host metabolism), (2) their selective activity against both Gram-positive and Gram-negative pathogens (including antibiotic resistant strains) and mycobacteria, (3) the limited resistance development reported so far. The present review summarizes and discusses the potential applications of endolysins as new anti-microbials.

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Chemical biology probes of mammalian GLUT structure and function

Biochemical Journal ◽

10.1042/bcj20170677 ◽

2018 ◽

Vol 475 (22) ◽

pp. 3511-3534 ◽

Cited By ~ 17

Author(s):

Geoffrey D. Holman

Keyword(s):

Drug Targets ◽

Chemical Biology ◽

Metabolic Diseases ◽

Cell Metabolism ◽

Structure And Function ◽

Research Groups ◽

And Function ◽

Diabetes And Obesity ◽

Potential Drug Targets

The structure and function of glucose transporters of the mammalian GLUT family of proteins has been studied over many decades, and the proteins have fascinated numerous research groups over this time. This interest is related to the importance of the GLUTs as archetypical membrane transport facilitators, as key limiters of the supply of glucose to cell metabolism, as targets of cell insulin and exercise signalling and of regulated membrane traffic, and as potential drug targets to combat cancer and metabolic diseases such as type 2 diabetes and obesity. This review focusses on the use of chemical biology approaches and sugar analogue probes to study these important proteins.

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Discovery and Characterization of QPT-1, the Progenitor of a New Class of Bacterial Topoisomerase Inhibitors

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00247-08 ◽

2008 ◽

Vol 52 (8) ◽

pp. 2806-2812 ◽

Cited By ~ 63

Author(s):

Alita A. Miller ◽

Gordon L. Bundy ◽

John E. Mott ◽

Jill E. Skepner ◽

Timothy P. Boyle ◽

...

Keyword(s):

High Throughput Screening ◽

Resistant Bacteria ◽

Infection Model ◽

Antibacterial Drug ◽

Synthetic Compound ◽

Antibiotic Resistant ◽

New Class ◽

Mechanism Of Inhibition ◽

Barbituric Acid Derivative

ABSTRACT QPT-1 was discovered in a compound library by high-throughput screening and triage for substances with whole-cell antibacterial activity. This totally synthetic compound is an unusual barbituric acid derivative whose activity resides in the (−)-enantiomer. QPT-1 had activity against a broad spectrum of pathogenic, antibiotic-resistant bacteria, was nontoxic to eukaryotic cells, and showed oral efficacy in a murine infection model, all before any medicinal chemistry optimization. Biochemical and genetic characterization showed that the QPT-1 targets the β subunit of bacterial type II topoisomerases via a mechanism of inhibition distinct from the mechanisms of fluoroquinolones and novobiocin. Given these attributes, this compound represents a promising new class of antibacterial agents. The success of this reverse genomics effort demonstrates the utility of exploring strategies that are alternatives to target-based screens in antibacterial drug discovery.

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