Metabolomics in the natural products field – a gateway to novel antibiotics

Synergizing the potential of bacterial genomics and metabolomics to find novel antibiotics

Chemical Science ◽

10.1039/d0sc06919a ◽

2021 ◽

Author(s):

Fabian Panter ◽

Chantal D. Bader ◽

Rolf Müller

Keyword(s):

Natural Products ◽

Antimicrobial Resistance ◽

Public Concern ◽

Bacterial Genomics ◽

Technological Developments ◽

Novel Antibiotics

Antimicrobial resistance is a major public concern and novel antibiotics are largely based on natural products. We summarize recent analytical and genome based technological developments that gain increasing importance in the natural products field.

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Bioprospecting for antituberculosis natural products – A review

Open Chemistry ◽

10.1515/chem-2021-0095 ◽

2021 ◽

Vol 19 (1) ◽

pp. 1074-1088

Author(s):

Olabisi Flora Davies-Bolorunduro ◽

Abraham Ajayi ◽

Isaac Adeyemi Adeleye ◽

Alfinda Novi Kristanti ◽

Nanik Siti Aminah

Keyword(s):

Natural Products ◽

Mycobacterium Tuberculosis ◽

High Throughput Screening ◽

Antitubercular Drug ◽

Natural Sources ◽

Resource Limited ◽

Novel Drugs ◽

Mdr Tb ◽

Drug Leads ◽

Novel Antibiotics

Abstract There has been an increase in the reported cases of tuberculosis, a disease caused by Mycobacterium tuberculosis, which is still currently affecting most of the world’s population, especially in resource-limited countries. The search for novel antitubercular chemotherapeutics from underexplored natural sources is therefore of paramount importance. The renewed interest in studies related to natural products, driven partly by the growing incidence of MDR-TB, has increased the prospects of discovering new antitubercular drug leads. This is because most of the currently available chemotherapeutics such as rifampicin and capreomycin used in the treatment of TB were derived from natural products, which are proven to be an abundant source of novel drugs used to treat many diseases. To meet the global need for novel antibiotics from natural sources, various strategies for high-throughput screening have been designed and implemented. This review highlights the current antitubercular drug discovery strategies from natural sources.

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Enzyme alchemy: cell-free synthetic biochemistry for natural products

Emerging Topics in Life Sciences ◽

10.1042/etls20190083 ◽

2019 ◽

Vol 3 (5) ◽

pp. 529-535 ◽

Cited By ~ 1

Author(s):

Simon J. Moore

Keyword(s):

Natural Products ◽

Total Synthesis ◽

Natural Product ◽

Living Cell ◽

Chemical Biology ◽

Low Cost ◽

Challenges And Opportunities ◽

Whole Cell Biotransformation ◽

Synthesis Routes ◽

Novel Antibiotics

Cell-free synthetic biochemistry aims to engineer chemical biology by exploiting biosynthetic dexterity outside of the constraints of a living cell. One particular use is for making natural products, where cell-free systems have initially demonstrated feasibility in the biosynthesis of a range of complex natural products classes. This has shown key advantages over total synthesis, such as increased yield, enhanced regioselectivity, use of reduced temperatures and less reaction steps. Uniquely, cell-free synthetic biochemistry represents a new area that seeks to advance upon these efforts and is particularly useful for defining novel synthetic pathways to replace natural routes and optimising the production of complex natural product targets from low-cost precursors. Key challenges and opportunities will include finding solutions to scaled-up cell-free biosynthesis, as well as the targeting of high value and toxic natural products that remain challenging to make either through whole-cell biotransformation platforms or total synthesis routes. Although underexplored, cell-free synthetic biochemistry could also be used to develop ‘non-natural’ natural products or so-called xenobiotics for novel antibiotics and drugs, which can be difficult to engineer directly within a living cell.

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Loci Encoding Compounds Potentially Active against Drug-Resistant Pathogens amidst a Decreasing Pool of Novel Antibiotics

Applied and Environmental Microbiology ◽

10.1128/aem.01438-19 ◽

2019 ◽

Vol 85 (23) ◽

Author(s):

Joseph Basalla ◽

Payel Chatterjee ◽

Elizabeth Burgess ◽

Mahnur Khan ◽

Emily Verbrugge ◽

...

Keyword(s):

Natural Products ◽

Gene Clusters ◽

Multidrug Resistant ◽

Antagonistic Activity ◽

World Health ◽

Drug Resistant ◽

Content Type ◽

Carbapenem Resistant ◽

Health Organization ◽

Novel Antibiotics

ABSTRACT Since the discovery of penicillin, microbes have been a source of antibiotics that inhibit the growth of pathogens. However, with the evolution of multidrug-resistant (MDR) strains, it remains unclear if there is an abundant or limited supply of natural products to be discovered that are effective against MDR isolates. To identify strains that are antagonistic to pathogens, we examined a set of 471 globally derived environmental Pseudomonas strains (env-Ps) for activity against a panel of 65 pathogens including Achromobacter spp., Burkholderia spp., Pseudomonas aeruginosa, and Stenotrophomonas spp. isolated from the lungs of cystic fibrosis (CF) patients. From more than 30,000 competitive interactions, 1,530 individual inhibitory events were observed. While strains from water habitats were not proportionate in antagonistic activity, MDR CF-derived pathogens (CF-Ps) were less susceptible to inhibition by env-Ps, suggesting that fewer natural products are effective against MDR strains. These results advocate for a directed strategy to identify unique drugs. To facilitate discovery of antibiotics against the most resistant pathogens, we developed a workflow in which phylogenetic and antagonistic data were merged to identify strains that inhibit MDR CF-Ps and subjected those env-Ps to transposon mutagenesis. Six different biosynthetic gene clusters (BGCs) were identified from four strains whose products inhibited pathogens including carbapenem-resistant P. aeruginosa. BGCs were rare in databases, suggesting the production of novel antibiotics. This strategy can be utilized to facilitate the discovery of needed antibiotics that are potentially active against the most drug-resistant pathogens. IMPORTANCE Carbapenem-resistant P. aeruginosa is difficult to treat and has been deemed by the World Health Organization as a priority one pathogen for which antibiotics are most urgently needed. Although metagenomics and bioinformatic studies suggest that natural bacteria remain a source of novel compounds, the identification of genes and their products specific to activity against MDR pathogens remains problematic. Here, we examine water-derived pseudomonads and identify gene clusters whose compounds inhibit CF-derived MDR pathogens, including carbapenem-resistant P. aeruginosa.

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From bugs to drugs: Combating antimicrobial resistance by discovering novel antibiotics

The Journal of Infection in Developing Countries ◽

10.3855/jidc.10108 ◽

2018 ◽

Vol 12 (02.1) ◽

pp. 3S

Author(s):

Antoine Abou Fayad ◽

Dana Itani ◽

Mariam Miari ◽

Arax Tanelian ◽

Sereen Iweir ◽

...

Keyword(s):

Escherichia Coli ◽

Antibacterial Activity ◽

Natural Products ◽

Antimicrobial Resistance ◽

Soil Microorganisms ◽

Soil Samples ◽

16S Rrna Analysis ◽

Strain Isolation ◽

Bacillus Subtilis Atcc ◽

Novel Antibiotics

Introduction: Antimicrobial resistance (AMR) is emerging at an alarming rate as mortality due to resistant pathogens could rise to 10 million per year by 2050. Since AMR is against all clinically utilized antibiotics, finding novel antimicrobials with unexploited targets remains the main goal worldwide. Soil microorganisms produce natural products as a significant number of drugs in clinical use are derived from these metabolites. Actinomycetes and Myxobacteria are soil dwelling microorganisms that produce secondary metabolites to be screened for antibacterial activity. More than 80% of clinically utilized antibiotics are either natural products or natural product-derived molecules such as vancomycin, teicoplanin, daptomycin, and tetracycline. This study aims to isolate and identify novel antimicrobials from Actinomycetes and Myxobacteria. Methodology: Soil samples were collected from several areas in Lebanon. Samples were serially diluted for Actinomycetes isolation and boiled for Myxobacteria extraction, then plated on suitable media. Colonies obtained were purified and subjected to genomic DNA extraction then 16s rRNA analysis. Novel isolates were tested for their antimicrobial activity against Gram-positive Bacillus subtilis (ATCC 6051), Staphylococcus aureus (ATCC 29213, Newman, N315), Enterococcus faecalis (ATCC 19433), and Enterococcus faecium (DSMZ 17050), and Gram-negative Escherichia coli (ATCC 9637), Klebsiella pneumoniae (DSMZ), Pseudomonas aeruginosa (ATCC 27853, MEXAB), and Acinetobacter baumannii (ATCC 15308). Results: Strain isolation and cultivation yielded a number of novel isolates whose extracts demonstrated strong antibacterial activity against pathogens including MRSA, VRE, and Escherichia coli (ATCC 9637). Conclusion: Our efforts now focus on purifying these compounds, elucidate their structures and study their mode of action.

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