Mark S. Butler

Natural products to drugs: natural product-derived compounds in clinical trials

Natural product and natural product-derived compounds that are being evaluated in clinical trials or in registration (current 31 December 2004) have been reviewed. Natural product derived drugs launched in the United States of America, Europe and Japan since 1998 and new natural product templates discovered since 1990 are discussed.

A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases.

The NOD-like receptor (NLR) family, pyrin domain–containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimers disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle–Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.

Antibiotics in the clinical pipeline in 2011

The emergence of multi-drug-resistant bacteria and the lack of new antibiotics in the antibiotic drug development pipeline, especially those with new modes of action, is a major health concern. This review lists the 20 new antibiotics launched since 2000 and records the 40 compounds currently in active clinical development. Compounds in the pipeline from new antibiotic classes are reviewed in detail with reference to their development status, mode of action, spectrum of activity and lead discovery. In addition, the NP or synthetic derivation is discussed, with activity against Gram-negative bacteria highlighted.

Glycopeptide antibiotics: back to the future

Glycopeptide antibiotics have been a key weapon in the fight against bacterial infections for over half a century, with the progenitors, vancomycin (1) and teicoplanin (2), still used extensively. The increased occurrence of resistance and the effectiveness of these ‘last resort’ treatments for Gram-positive infections has led to the discovery and clinical development of second generation, semisynthetic lipoglycopeptide derivatives such as telavancin (3), dalbavancin (4) and oritavancin (5), which all possess broader spectra of activity and improved pharmacokinetic properties. Two of these new antibiotics, telavancin (3) and dalbavancin (4), were approved in the past 5 years and the third, oritavancin (5), is awaiting regulatory approval. In this review, the discovery, development and associated resistance of vancomycin (1) and teicoplanin (2), and semi-synthetic glycopeptides, telavancin (3), dalbavancin (4) and oritavancin (5), are detailed. The clinical implications of glycopeptide resistance, especially vancomycin (1), as well as the future prospects for current glycopeptide drugs and the development of new glycopeptides are discussed.

Antibiotics in the clinical pipeline at the end of 2015

There is growing global recognition that the continued emergence of multidrug-resistant bacteria poses a serious threat to human health. Action plans released by the World Health Organization and governments of the UK and USA in particular recognize that discovering new antibiotics, particularly those with new modes of action, is one essential element required to avert future catastrophic pandemics. This review lists the 30 antibiotics and two β-lactamase/β-lactam combinations first launched since 2000, and analyzes in depth seven new antibiotics and two new β-lactam/β-lactamase inhibitor combinations launched since 2013. The development status, mode of action, spectra of activity and genesis (natural product, natural product-derived, synthetic or protein/mammalian peptide) of the 37 compounds and six β-lactamase/β-lactam combinations being evaluated in clinical trials between 2013 and 2015 are discussed. Compounds discontinued from clinical development since 2013 and new antibacterial pharmacophores are also reviewed.

Mother Nature’s gifts to diseases of man: the impact of natural products on anti-infective, anticholestemics and anticancer drug discovery

This chapter is designed to demonstrate that compounds derived from nature are still in the forefront of drug discovery in diseases such as microbial and parasitic infections, carcinomas of many types and control of cholesterol/lipids in man. In each disease area we have provided short discussions of past, present and future agents, in general only considering compounds currently in clinical Phase II or later, that were/are derived from natures chemical skeletons. Finishing with a discussion of the current and evolving role(s) of microbes (bacteria and fungi) in the production of old and new agents ostensibly produced by higher organisms.

Extraordinary levels of cadmium and zinc in a marine sponge,Tedania charcoti Topsent: inorganic chemical defense agents

The Antarctic marine spongeTedania charcoti has been shown to contain extraordinarily high natural concentrations of cadmium and zinc, which have in turn been correlated to the ability of the crude ethanol extract to modulate protein phosphorylation in chicken forebrain and to inhibit the growth of several test bacteria.

Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B

The polymyxin lipodecapeptides colistin and polymyxin B have become last resort therapies for infections caused by highly drug-resistant Gram-negative bacteria. Unfortunately, their utility is compromised by significant nephrotoxicity and polymyxin-resistant bacterial strains. We have conducted a systematic activity–toxicity investigation by varying eight of the nine polymyxin amino acid free side chains, preparing over 30 analogues using a novel solid-phase synthetic route. Compounds were tested against a panel of Gram-negative bacteria and counter-screened for in vitro cell toxicity. Promising compounds underwent additional testing against primary kidney cells isolated from human kidneys to better predict their nephrotoxic potential. Many of the new compounds possessed equal or better antimicrobial potency compared to polymyxin B, and some were less toxic than polymyxin B and colistin against mammalian HepG2 cells and human primary kidney cells. These initial structure–activity and structure–toxicity studies set the stage for further improvements to the polymyxin class of antibiotics.

Surface changes and polymyxin interactions with a resistant strain of Klebsiella pneumoniae

This study examines the interaction of polymyxin B and colistin with the surface and outer membrane components of a susceptible and resistant strain of Klebsiella pneumoniae. The interaction between polymyxins and bacterial membrane and isolated LPS from paired wild type and polymyxin-resistant strains of K. pneumoniae were examined with N-phenyl-1-naphthylamine (NPN) uptake, fluorometric binding and thermal shift assays, lysozyme and deoxycholate sensitivity assays, and by 1H NMR. LPS from the polymyxin-resistant strain displayed a reduced binding affinity for polymyxins B and colistin in comparison with the wild type LPS. The outer membrane NPN permeability of the resistant strain was greater compared with the susceptible strain. Polymyxin exposure enhanced the permeability of the outer membrane of the wild type strain to lysozyme and deoxycholate, whereas polymyxin concentrations up to 32 mg/ml failed to permeabilize the outer membrane of the resistant strain. Zeta potential measurements revealed that mid-logarithmic phase wild type cells exhibited a greater negative charge than the mid-logarithmic phase-resistant cells. Taken together, our findings suggest that the resistant derivative of K. pneumoniae can block the electrostatically driven first stage of polymyxin action, which thereby renders the hydrophobically driven second tier of polymyxin action on the outer membrane inconsequential.

Organic geochemical and geochemical studies of Inner Great Barrier Reef sediments—IV. Identification of terrigenous and marine sourced inputs☆

Abstract Surface sediments sampled along a transect Cairns Harbour and Arlington Reef together with a core taken at the 20 m depth line have been analysed for geochemical parameters and organic geochemical biomarkers. The data show a maximum occurs in the deposition of silty sediment at 11 km from the land. Particle size, iron and calcium concentrations are reported for the surface sediments of the transect. For the core, these parameters as well as the water content show a sedimentation discontinuity at 4–8 cm in the sub-surface. Iron content (an indicator of terrigenously derived sediment) correlates well with the biomarker taraxerol (a pentacyclic triterpenoid alcohol) a strong marker for terrigenously derived organic material. Medium chain length fatty acid profiles (from marine organisms) correlate with algal-derived sterol distributions suggesting an input of marine origin which maximizes at the sediment surface. Both marine and terrigenous biomarkers show a secondary maximum at 4–8 cm below the surface. Taken with the geochemical parameters, these results suggest that a cyclonic or flood event in the recent past is responsible for the sedimentary discontinuity. On the basis of phospholipid content, the biomass of intact cells in surface sediments increases with distance from the land along the transect, possibly reflecting decreasing water turbidity. The depth profile in the sediment suggests that biological diagenesis can be expected to a depth of about 8 cm, which is a significant observation in relation to the stability of organic compounds in these near shore marine tropical sediments.