A Resistance-Evading Antibiotic for Treating Anthrax.

The antimicrobial resistance crisis (AMR) is associated with millions of deaths and undermines the franchise of medicine. Of particular concern is the threat of bioweapons, exemplified by anthrax. Introduction of novel antibiotics helps mitigate AMR, but does not address the threat of bioweapons with engineered resistance.

An antibiotic from an uncultured bacterium binds to an immutable target.

Antimicrobial resistance is a leading mortality factor worldwide. Here, we report the discovery of clovibactin, an antibiotic isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant Gram-positive bacterial pathogens without detectable resistance.

A new antibiotic from an uncultured bacterium binds to an immutable target.

Antimicrobial resistance is a leading mortality factor worldwide. Here we report the discovery of clovibactin, a new antibiotic, isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant bacterial pathogens without detectable resistance.

Synthesis and Stereochemical Determination of the Peptide Antibiotic Novo29.

This paper describes the synthesis and stereochemical determination of Novo29 (clovibactin), a new peptide antibiotic that is related to teixobactin and is active against Gram-positive bacteria. Novo29 is an eight-residue depsipeptide that contains the noncanonical amino acid hydroxyasparagine of hitherto undetermined stereochemistry in a macrolactone ring. The amino acid building blocks Fmoc-(2,3)-hydroxyasparagine-OH and Fmoc-(2,3)-hydroxyasparagine-OH were synthesized from (,)- and (,)-diethyl tartrate.

Teixobactin kills bacteria by a two-pronged attack on the cell envelope.

Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance. Teixobactin represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan.

Teixobactin Provides Protection against Inhalation Anthrax in the Rabbit Model.

The use of antibiotics is a vital means of treating infections caused by the bacteria . Importantly, with the potential future use of multidrug-resistant strains of as bioweapons, new antibiotics are needed as alternative therapeutics. In this blinded study, we assessed the protective efficacy of teixobactin, a recently discovered antibiotic, against inhalation anthrax infection in the adult rabbit model.

Novel Antimicrobials from Uncultured Bacteria Acting against Mycobacterium tuberculosis.

, which causes tuberculosis (TB), is estimated to infect one-third of the world's population. The overall burden and the emergence of drug-resistant strains of underscore the need for new therapeutic options against this important human pathogen. Our recent work demonstrated the success of natural product discovery in identifying novel compounds with efficacy against Here, we improve on these methods by combining improved isolation and selective screening to identify three new anti-TB compounds: streptomycobactin, kitamycobactin, and amycobactin.

A new antibiotic kills pathogens without detectable resistance.

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.

Lassomycin, a ribosomally synthesized cyclic peptide, kills mycobacterium tuberculosis by targeting the ATP-dependent protease ClpC1P1P2.

Languishing antibiotic discovery and flourishing antibiotic resistance have prompted the development of alternative untapped sources for antibiotic discovery, including previously uncultured bacteria. Here, we screen extracts from uncultured species against Mycobacterium tuberculosis and identify lassomycin, an antibiotic that exhibits potent bactericidal activity against both growing and dormant mycobacteria, including drug-resistant forms of M. tuberculosis, but little activity against other bacteria or mammalian cells.

Fragment screening using capillary electrophoresis (CEfrag) for hit identification of heat shock protein 90 ATPase inhibitors.

CEfrag is a new fragment screening technology based on affinity capillary electrophoresis (ACE). Here we report on the development of a mobility shift competition assay using full-length human heat shock protein 90α (Hsp90α), radicicol as the competitor probe ligand, and successful screening of the Selcia fragment library. The CEfrag assay was able to detect weaker affinity (IC(50) >500 µM) fragments than were detected by a fluorescence polarization competition assay using FITC-labeled geldanamycin.

Exploiting new approaches for natural product drug discovery in the biotechnology industry.

In recent years, large pharmaceutical companies have significantly reduced or eliminated the search for new therapeutic agents from natural sources. In spite of the many successes from natural product drug discovery, these companies have chosen to focus on compound libraries as the source of new lead compounds. Smaller biotechnology companies are continuing the search for novel natural products by developing and employing new and innovative approaches.

A phthalide with in vitro growth inhibitory activity from an oidiodendron strain.

A screening campaign was implemented utilizing capillary electrophoresis as a primary assay to discover binders to the cancer target Akt1 from a crude natural extract library. Fungal extracts with binding activities were characterized for biochemical inhibition of Akt1 to phosphorylate the downstream substrate protein Bad. One of the crude extracts with bioactivity selected for isolation and structure elucidation from fermentation of the fungal culture Oidiodendron sp.

Capillary electrophoretic approach to screen for enzyme inhibitors in natural extracts.

This paper demonstrates development of electrophoretically mediated micro analysis (EMMA), for screening protein tyrosine phosphatase (PTP) inhibitors in natural extracts. It is demonstrated that capillary electrophoresis (CE) separation of the substrate and the product allows for using the assay in an on-column format to monitor the reaction without typically used fluorogenic substrates. Michaelis-Menten kinetics parameters calculated based on the EMMA results (Km = 1.

Affinity capillary electrophoresis for the screening of novel antimicrobial targets.

The increasing number of multiantibiotic-resistant organisms, including methicillin-resistant Staphylococcus aureus (MRSA), requires the development of novel chemotherapies that are structurally distinct and exempt from current resistance mechanisms. Bioinformatics data mining of microbial genomes has revealed numerous previously unexploited essential open reading frames (ORFs) of unknown biochemical function. The potential of these proteins as screening targets is not readily apparent because most screening technologies rely on knowledge of biological function.

Affinity capillary electrophoresis analyses of protein-protein interactions in target-directed drug discovery.

Protein-protein interactions are instrumental in virtually all biological processes and their understanding will shed light on designing novel and effective drugs for therapeutic interventions targeting the pathways in which they function. Protein-protein interactions have been studied using many genetic and biochemical methods, most recently, affinity capillary electrophoresis (ACE). We used ACE as a high-throughput screening assay to establish and define binding interactions between a therapeutic target protein and chemical entities from natural product or synthetic chemical libraries.