Novel Screen Methodologies for Identification of New Microbial Metabolites
1 Introduction
75
1.1 The Value of Microbial Chemical Diversity
Microorganisms produce an impressive range of secondary metabolites representing a rich diversity of chemical types. Some of these compounds have proved
to be of great economic importance, not only to the pharmaceutical industry,
but also as sources of new leads for the agrochemical sector. Organised exploitation of microorganisms as a source of chemical diversity began in the 1940s and
1950s as the significance of the discovery of penicillin was realised [ 1, 2]. During
this period, screening programmes for antimicrobial activity were successful in
identifying many new antibiotics such as the cephalosporins, tetracyclines and
aminoglycosides. The search for microbial metabolites with other biological
activities began in the late 1960s with the development of assays for the
discovery of enzyme inhibitors of microbial origin [3]. This led to the discovery
of many new compounds including two currently successful clinical agents,
clavulanic acid and mevinolin. The former is a B-lactamase inhibitor [4] which
is used in combination with ~-lactam antibiotics in antibacterial therapy whilst
the latter is the first of a series of related hydroxymethylglutaryl- CoA reductase
inhibitors for treatment of hypercholesterolemia [5]. Further phamacologically
significant natural products include the immunosuppressants cycloporin A [-6]
and FK506 [7].
The number of reported microbial metabolites with non-antibiotic biological activities has increased steadily since the early 1970s, and by 1990 it
exceeded the number of antibiotics reported [8]. Advances in biotechnology and
rapid progress with the human genome project are providing access to a wide
range of new molecular targets implicated in various human disease states [9],
and this explosion in target identification will yield many new opportunities for
the exploitation of the molecular diversity generated from natural product
sources. The following is a survey of assays used in the search for phamacologically active microbial metabolites during the period 1988-1995, together
with some observations on current trends in assay technology for new drug
discovery.
1.2 Demands of Assays Designed for Testing Microbial Samples
A diverse array of assays has been, and is being, used in microbial screening
programmes to detect novel lead compounds with pharmacological activities.
Such assays must fulfil a number of criteria if this search for potential new drugs
is to be successful.
Firstly, they must be designed to function in the presence of samples with
a range of physico-chemical properties. Various sample preparation techniques
are used to generate libraries for screening, resulting in test mixtures which may
1 Introduction
75
1.1 The Value of Microbial Chemical Diversity
Microorganisms produce an impressive range of secondary metabolites representing a rich diversity of chemical types. Some of these compounds have proved
to be of great economic importance, not only to the pharmaceutical industry,
but also as sources of new leads for the agrochemical sector. Organised exploitation of microorganisms as a source of chemical diversity began in the 1940s and
1950s as the significance of the discovery of penicillin was realised [ 1, 2]. During
this period, screening programmes for antimicrobial activity were successful in
identifying many new antibiotics such as the cephalosporins, tetracyclines and
aminoglycosides. The search for microbial metabolites with other biological
activities began in the late 1960s with the development of assays for the
discovery of enzyme inhibitors of microbial origin [3]. This led to the discovery
of many new compounds including two currently successful clinical agents,
clavulanic acid and mevinolin. The former is a B-lactamase inhibitor [4] which
is used in combination with ~-lactam antibiotics in antibacterial therapy whilst
the latter is the first of a series of related hydroxymethylglutaryl- CoA reductase
inhibitors for treatment of hypercholesterolemia [5]. Further phamacologically
significant natural products include the immunosuppressants cycloporin A [-6]
and FK506 [7].
The number of reported microbial metabolites with non-antibiotic biological activities has increased steadily since the early 1970s, and by 1990 it
exceeded the number of antibiotics reported [8]. Advances in biotechnology and
rapid progress with the human genome project are providing access to a wide
range of new molecular targets implicated in various human disease states [9],
and this explosion in target identification will yield many new opportunities for
the exploitation of the molecular diversity generated from natural product
sources. The following is a survey of assays used in the search for phamacologically active microbial metabolites during the period 1988-1995, together
with some observations on current trends in assay technology for new drug
discovery.
1.2 Demands of Assays Designed for Testing Microbial Samples
A diverse array of assays has been, and is being, used in microbial screening
programmes to detect novel lead compounds with pharmacological activities.
Such assays must fulfil a number of criteria if this search for potential new drugs
is to be successful.
Firstly, they must be designed to function in the presence of samples with
a range of physico-chemical properties. Various sample preparation techniques
are used to generate libraries for screening, resulting in test mixtures which may