Productos Naturales

biochemical pharmacology 71 (2006) 919–929

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/biochempharm

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Natural products — The future scaffolds for novel antibiotics?
Mark S. Butler *, Antony D. Buss
MerLion Pharmaceuticals, 1 Science Park Road, The Capricorn #05-01, Singapore Science Park II, Singapore 117528, Singapore

article info
Articlehistory: Received 25 August 2005 Accepted 5 October 2005

abstract
Natural products have played a pivotal role in antibiotic drug discovery with most antibacterial drugs being derived from a natural product or natural product lead. However, the rapid onset of resistance to most antibacterial drugs diminishes their effectiveness considerably and necessitates a constant supply of new antibiotics foreffective treatment of infections. The natural product templates of actinonin, pleuromutilin, ramoplanin and

Keywords: Natural product Clinical trial Template Antibacterial Antibiotic Assay

tiacumicin B, which are compounds undergoing clinical evaluation, represent templates not found in currently marketed antibacterial drugs. In addition, the new templates present in the recently discoveredlead antibacterials arylomycin, GE23077, mannopeptimycin, muraymycin/caprazamycin, nocathiacin and ECO-0501, are discussed. Despite extensive efforts to identify antibiotic leads from molecular targets, only the peptide deformylase inhibitor LBM-415 is currently in clinical trials. It is proposed that new antibacterial assays which combine cell-based screening with molecular targets could offerbetter prospects for lead discovery. # 2005 Elsevier Inc. All rights reserved.

1.

Introduction

The introduction of the sulphonamide antibiotics in the 1930s and penicillin in the 1940s revolutionised medicinal practice by dramatically decreasing the fatality rates associated with bacterial infections [1–3]. These discoveries led to a concerted search for new antibacterial drugs during thefollowing 30 years and resulted in the discovery of most of the antibacterial drug classes known today, many of which were derived from natural product leads (Table 1) [1,4,5]. Given this success, it is surprising to note that only three new antibacterial classes, the topical antibiotic mupirocin in 1985, the oxazolidinone linezolid in 2000 and the lipopeptide daptomycin in 2003, have entered themarket since 1970. Over the past 20 years, there has been a 56% decline in the number of antibiotics approved annually by the Food and Drug Administration (FDA) and over the last decade, only 22 new antibacterial drugs have been launched (Table 2) [6–9]. The 12 natural product-derived drugs

belong to five different structure classes (b-lactam, streptogramin, macrolide, tetracycline anddaptomycin), while the 10 synthetic drugs launched belong to only two antibacterial classes, with the quinolone class accounting for nine of these drugs. The prevalence of natural product-derived antibacterial drugs may be due to the evolution of secondary metabolites as biologically active chemicals that conferred selectional advantages to the producing organisms. Natural products also are likely to haveevolved to penetrate cell membranes and interact with specific protein targets [10]. In addition, natural products have an element of structural complexity which is required for the inhibition of many antibacterial protein targets. Relevant reviews on the role of natural products in modern drug discovery [11,12], natural productderived compounds in clinical trials [13] and compounds in antibacterialclinical trials have been published recently [14–17].

* Corresponding author. Tel.: +65 6829 5611; fax: +65 6829 5601. E-mail address: mark@merlionpharma.com (M.S. Butler). 0006-2952/$ – see front matter # 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.bcp.2005.10.012

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biochemical pharmacology 71 (2006) 919–929

Table 1 – Antibiotic class with approximate year of clinical...