Natural products and their derivatives have historically been invaluable as a source of therapeutic agents. However, in the past decade, research into natural products in the pharmaceutical industry has declined, owing to issues such as the lack of compatibility of traditional natural-product extract libraries with high-throughput screening. However, as discussed in this review, recent technological advances that help to address these issues, coupled with unrealized expectations from current lead-generation strategies, have led to a renewed interest in natural products in drug discovery.

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The muraymycins, a family of nucleoside-lipopeptide antibiotics, were purified from the extract of Streptomyces sp. LL-AA896. The antibiotics were purified by chromatographic methods and characterized by NMR spectroscopy, degradation studies, and mass spectrometry. The structures of 19 compounds were established. The muraymycins constitute a new antibiotic family whose core structure contains a glycosylated uronic acid derivative joined by an aminopropane group to a hexahydro-2-imino-4-pyrimidylglycyl residue (epicapreomycidine) containing dipeptide that is further extended by a urea-valine moiety. Members of this family show broad-spectrum in vitro antimicrobial activity against a variety of clinical isolates (MIC 2 to >64 mug/mL). The muraymycins inhibited peptidoglycan biosynthesis. The fatty acid substituent and the presence or absence of the amino sugar play important roles in biological activity. One of the most active compounds, muraymycin A1, demonstrated protection in vivo against Staphylococcus aureus infection in mice (ED50 1.1 mg/kg).

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The pharmaceutical industry is facing an ever increasing challenge to deliver safer and more effective medicines. Traditionally, drug discovery programs were driven solely by potency, regardless of the properties. As a result, the development of non-drug-like molecules was costly, had high risk and low success rate. To meet the challenges, the bar has been rising higher for drug candidates. They not only need to be active, but also drug-like to be advanced to clinical development. Drug-like properties, such as solubility, permeability, metabolic stability and transporter effects are of critical importance for the success of drug candidates. They affect oral bioavailability, metabolism, clearance, toxicity, as well as in vitro pharmacology. Insoluble and impermeable compounds can result in erroneous biological data and unreliable SAR in enzyme and cell-based assays. Rapid metabolism by enzymes and high efflux by transporters can lead to high clearance, short half-life, low systemic exposure and inadequate efficacy. Early property information helps teams make informed decisions and avoids wasting precious resources. Structure-property relationships are essential to guide structural modification to improve properties. High throughput ADME/TOX assays have been implemented and are being widely used to drive drug discovery projects in parallel with activity screening. Property design has become an integrated and inseparable part of the modern drug discovery paradigm. The approach has been proven to be a winning strategy.

A series of novel antibiotics with activity against methicillin-resistant staphylococci and vancomycin-resistant enterococci has been purified, and their structures have been characterized using spectroscopic analyses and chemical conversions. These antibiotics, designated mannopeptimycins alpha-epsilon (1-5), are glycosylated cyclic hexapeptides containing two stereoisomers of an unprecedented amino acid, alpha-amino-beta-[4'-(2'-iminoimidazolidinyl)]-beta-hydroxypropionic acid (Aiha), as a distinguishing feature. The cyclic peptide core of these antibiotics is attached to a mannosyl monosaccharide moiety in 2 and to mannosyl monosaccharide and disaccharide moieties in 1, 3, 4, and 5. The presence and position of an isovaleryl group in the terminal mannose (Man-B) in 3-5 are critical for retaining antibacterial potency.

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The structure of a new dibenzodiazepine alkaloid, diazepinomicin (1), isolated from the culture of a marine actinomycete of the genus Micromonospora was characterized using spectroscopic methods. Diazepinomicin represents a unique molecular class composed of a dibenzodiazepine core linked to a farnesyl side chain.