Thoughts and facts about antibiotics: Where we are now and where we are heading

Bérdy, János

doi:10.1038/ja.2012.27

Cited by 904 publications

(620 citation statements)

References 51 publications

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“…It is estimated that during the golden era (1940–1970) of microbial natural product screening, tens of millions of soil microorganisms have been screened (Baltz, 2005), an enormous effort that provided the vast majority of microbial metabolites known today (Bérdy, 2005, 2012; Monciardini et al ., 2014). These substances include widely prescribed antibacterial therapeutics, such as erythromycin, streptomycin, tetracycline, vancomycin and chemotherapeutic drugs such as doxorubicin.…”

Section: Introductionmentioning

confidence: 99%

Antibiotic drug discovery

Wohlleben

Mast

Stegmann

et al. 2016

Microbial Biotechnology

135

113

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SummaryDue to the threat posed by the increase of highly resistant pathogenic bacteria, there is an urgent need for new antibiotics; all the more so since in the last 20 years, the approval for new antibacterial agents had decreased. The field of natural product discovery has undergone a tremendous development over the past few years. This has been the consequence of several new and revolutionizing drug discovery and development techniques, which is initiating a ‘New Age of Antibiotic Discovery’. In this review, we concentrate on the most significant discovery approaches during the last and present years and comment on the challenges facing the community in the coming years.

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Section: Introductionmentioning

confidence: 99%

Antibiotic drug discovery

Wohlleben

Mast

Stegmann

et al. 2016

Microbial Biotechnology

135

113

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“…First and foremost, phosphonates have great pharmaceutical potential, with a commercialization rate of 15% [three of 20 isolated compounds (15)]. This percentage is much higher than the 0.1% average estimated for natural products as a whole (16). The potent bioactivity of phosphonates derives from their chemical mimicry of essential metabolites, including phosphate esters and anhydrides, as well as carboxylate reaction intermediates (15).…”

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confidence: 99%

Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes

Gao

Doroghazi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

185

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Although natural products have been a particularly rich source of human medicines, activity-based screening results in a very high rate of rediscovery of known molecules. Based on the large number of natural product biosynthetic genes in microbial genomes, many have proposed "genome mining" as an alternative approach for discovery efforts; however, this idea has yet to be performed experimentally on a large scale. Here, we demonstrate the feasibility of large-scale, high-throughput genome mining by screening a collection of over 10,000 actinomycetes for the genetic potential to make phosphonic acids, a class of natural products with diverse and useful bioactivities. Genome sequencing identified a diverse collection of phosphonate biosynthetic gene clusters within 278 strains. These clusters were classified into 64 distinct groups, of which 55 are likely to direct the synthesis of unknown compounds. Characterization of strains within five of these groups resulted in the discovery of a new archetypical pathway for phosphonate biosynthesis, the first (to our knowledge) dedicated pathway for H-phosphinates, and 11 previously undescribed phosphonic acid natural products. Among these compounds are argolaphos, a broad-spectrum antibacterial phosphonopeptide composed of aminomethylphosphonate in peptide linkage to a rare amino acid N 5 -hydroxyarginine; valinophos, an N-acetyl L-Val ester of 2,3-dihydroxypropylphosphonate; and phosphonocystoximate, an unusual thiohydroximate-containing molecule representing a new chemotype of sulfur-containing phosphonate natural products. Analysis of the genome sequences from the remaining strains suggests that the majority of the phosphonate biosynthetic repertoire of Actinobacteria has been captured at the gene level. This dereplicated strain collection now provides a reservoir of numerous, as yet undiscovered, phosphonate natural products.natural products | genome mining | phosphonic acid | antibiotic

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“…Streptomycetes are a diverse group of filamentous bacteria that produce some two-thirds of all known antibiotics (8). Although the antibiotics they produce have classically been viewed as intermicrobial weapons (6,9), this perspective is increasingly questioned on two grounds (10)(11)(12)(13).…”

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confidence: 99%

Socially mediated induction and suppression of antibiosis during bacterial coexistence

Abrudan

Smakman

Grimbergen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

219

179

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Despite their importance for humans, there is little consensus on the function of antibiotics in nature for the bacteria that produce them. Classical explanations suggest that bacteria use antibiotics as weapons to kill or inhibit competitors, whereas a recent alternative hypothesis states that antibiotics are signals that coordinate cooperative social interactions between coexisting bacteria. Here we distinguish these hypotheses in the prolific antibiotic-producing genus Streptomyces and provide strong evidence that antibiotics are weapons whose expression is significantly influenced by social and competitive interactions between competing strains. We show that cells induce facultative responses to cues produced by competitors by (i) increasing their own antibiotic production, thereby decreasing costs associated with constitutive synthesis of these expensive products, and (ii) by suppressing antibiotic production in competitors, thereby reducing direct threats to themselves. These results thus show that although antibiotic production is profoundly social, it is emphatically not cooperative. Using computer simulations, we next show that these facultative strategies can facilitate the maintenance of biodiversity in a community context by converting lethal interactions between neighboring colonies to neutral interactions where neither strain excludes the other. Thus, just as bacteriocins can lead to increased diversity via rock-paper-scissors dynamics, so too can antibiotics via elicitation and suppression. Our results reveal that social interactions are crucial for understanding antibiosis and bacterial community dynamics, and highlight the potential of interbacterial interactions for novel drug discovery by eliciting pathways that mediate interference competition.

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Thoughts and facts about antibiotics: Where we are now and where we are heading

Cited by 904 publications

References 51 publications

Antibiotic drug discovery

Antibiotic drug discovery

Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes

Socially mediated induction and suppression of antibiosis during bacterial coexistence

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