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Aaron J. Peoples

Bio: Aaron J. Peoples is an academic researcher from NovoBiotic Pharmaceuticals. The author has contributed to research in topics: Lipid II & Antibiotics. The author has an hindex of 8, co-authored 20 publications receiving 2065 citations.
Topics: Lipid II, Antibiotics, Nocardia, Teixobactin, Medicine

Papers
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Journal ArticleDOI
22 Jan 2015-Nature
TL;DR: The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance, as well as several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors.
Abstract: Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.

1,964 citations

Journal ArticleDOI
TL;DR: It is shown that lassomycin binds to a highly acidic region of the ClpC1 ATPase complex and markedly stimulates its ATPase activity without stimulating ClpP1P2-catalyzed protein breakdown, which is essential for viability of mycobacteria.

301 citations

Journal ArticleDOI
TL;DR: Two novel antibiotics, neocitreamicins I and II, were isolated from a fermentation broth of a Nocardia strain and showed in vitro activity against Gram-positive bacteria including strains of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis.
Abstract: Two novel antibiotics, neocitreamicins I and II, were isolated from a fermentation broth of a Nocardia strain. This producing strain was obtained using an in situ diffusion chamber that facilitates the cultivation of soil microorganisms. The structures of neocitreamicins I and II were elucidated using UV, MS, and NMR data, and found to be related to the polycyclic xanthone antibiotics of the citreamicin class. The neocitreamicins showed in vitro activity against Gram-positive bacteria including strains of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis.

40 citations

Journal ArticleDOI
16 Apr 2015-Nature
TL;DR: This corrects the article to show that the Higgs boson genome is a “spatially aggregated “vessel” rather than an “ aggregating “ nucleus”, which indicates that theorems related to “consolidation” and “ghosting” are more likely to occur.
Abstract: Nature 517, 455–459 (2015); doi:10.1038/nature14098 In Fig. 3d of this Article, the ‘2:1’ and ‘1:1’ labels at the bottom of the panel were inadvertently switched during the production process; this figure has now been corrected in the online versions of the paper.

38 citations

Journal ArticleDOI
TL;DR: The mechanism of Teixobactin at the atomic level using a combination of solid-state NMR, microscopy, in vivo assays and molecular dynamics simulations was revealed in this paper .
Abstract: Abstract Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance 1–3 . Teixobactin 4 represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan 5 . Here we unravel the mechanism of teixobactin at the atomic level using a combination of solid-state NMR, microscopy, in vivo assays and molecular dynamics simulations. The unique enduracididine C-terminal headgroup of teixobactin specifically binds to the pyrophosphate-sugar moiety of lipid II, whereas the N terminus coordinates the pyrophosphate of another lipid II molecule. This configuration favours the formation of a β-sheet of teixobactins bound to the target, creating a supramolecular fibrillar structure. Specific binding to the conserved pyrophosphate-sugar moiety accounts for the lack of resistance to teixobactin 4 . The supramolecular structure compromises membrane integrity. Atomic force microscopy and molecular dynamics simulations show that the supramolecular structure displaces phospholipids, thinning the membrane. The long hydrophobic tails of lipid II concentrated within the supramolecular structure apparently contribute to membrane disruption. Teixobactin hijacks lipid II to help destroy the membrane. Known membrane-acting antibiotics also damage human cells, producing undesirable side effects. Teixobactin damages only membranes that contain lipid II, which is absent in eukaryotes, elegantly resolving the toxicity problem. The two-pronged action against cell wall synthesis and cytoplasmic membrane produces a highly effective compound targeting the bacterial cell envelope. Structural knowledge of the mechanism of teixobactin will enable the rational design of improved drug candidates.

24 citations


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Journal ArticleDOI
TL;DR: Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, they are still able to identify only two de novo combinatorials compounds approved as drugs in this 39-year time frame.
Abstract: This review is an updated and expanded version of the five prior reviews that were published in this journal in 1997, 2003, 2007, 2012, and 2016. For all approved therapeutic agents, the time frame has been extended to cover the almost 39 years from the first of January 1981 to the 30th of September 2019 for all diseases worldwide and from ∼1946 (earliest so far identified) to the 30th of September 2019 for all approved antitumor drugs worldwide. As in earlier reviews, only the first approval of any drug is counted, irrespective of how many "biosimilars" or added approvals were subsequently identified. As in the 2012 and 2016 reviews, we have continued to utilize our secondary subdivision of a "natural product mimic", or "NM", to join the original primary divisions, and the designation "natural product botanical", or "NB", to cover those botanical "defined mixtures" now recognized as drug entities by the FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or synthetic variations using their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from 1946 to 1980, of the 75 small molecules, 40, or 53.3%, are N or ND. In the 1981 to date time frame the equivalent figures for the N* compounds of the 185 small molecules are 62, or 33.5%, though to these can be added the 58 S* and S*/NMs, bringing the figure to 64.9%. In other areas, the influence of natural product structures is quite marked with, as expected from prior information, the anti-infective area being dependent on natural products and their structures, though as can be seen in the review there are still disease areas (shown in Table 2) for which there are no drugs derived from natural products. Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are still able to identify only two de novo combinatorial compounds (one of which is a little speculative) approved as drugs in this 39-year time frame, though there is also one drug that was developed using the "fragment-binding methodology" and approved in 2012. We have also added a discussion of candidate drug entities currently in clinical trials as "warheads" and some very interesting preliminary reports on sources of novel antibiotics from Nature due to the absolute requirement for new agents to combat plasmid-borne resistance genes now in the general populace. We continue to draw the attention of readers to the recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated"; thus we consider that this area of natural product research should be expanded significantly.

2,560 citations

Journal ArticleDOI
22 Jan 2015-Nature
TL;DR: The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance, as well as several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors.
Abstract: Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.

1,964 citations

Journal ArticleDOI
TL;DR: This work reviews strategies for natural product screening that harness the recent technical advances that have reduced technical barriers and assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products.
Abstract: Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein-protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.

1,822 citations

Journal ArticleDOI
21 Jan 2016-Nature
TL;DR: The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large as discussed by the authors, and the evolution and widespread distribution of antibiotic-resistant elements in bacterial pathogens has made diseases that were once easily treatable deadly again.
Abstract: The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large. The evolution and widespread distribution of antibiotic-resistance elements in bacterial pathogens has made diseases that were once easily treatable deadly again. Unfortunately, accompanying the rise in global resistance is a failure in antibacterial drug discovery. Lessons from the history of antibiotic discovery and fresh understanding of antibiotic action and the cell biology of microorganisms have the potential to deliver twenty-first century medicines that are able to control infection in the resistance era.

1,481 citations

Journal ArticleDOI
TL;DR: In this paper, the authors proposed a framework to combat the threat to human health and biosecurity from antimicrobial resistance, an understanding of its mechanisms and drivers is needed.

1,428 citations