Therapeutic Uses of Microorganisms

Introduction

The pharmaceutical industry is interested in microorganisms for three main reasons:

i) As contaminants of products, microorganisms potentially can cause illness to patients and/or product spoilage.

Identifying and quantifying contaminants of pharmaceutical products are not ideally addressed by conventional microbiological techniques. Certain characteristics of microorganisms may make their detection difficult: some can exist in resting or latent forms, the supreme example of this are bacterial endospores; under appropriate conditions microorganisms can multiply at a phenomenal rate, this means that unless very sensitive detection techniques are used, an initially unnoticed contaminant can grow to be a significant health or spoilage threat; some microorganisms have a very diverse metabolic repertoire, this means that they may unexpectedly be able to use components of a pharmaceutical product, including synthetic chemicals, as sources of nutrients.

Other approaches such as nucleic acid amplification and bioluminescence are slowly gaining acceptance or being investigated. Could microcalorimetry offer a realistic option?

ii) Microorganisms and eukaryotic cell lines are increasingly going to be the source of genetically-engineered and biotechnologically-produced human therapeutics. Expression of heterogenic proteins in cultured cells can, in many ways, be a fraught process. The imposition of this new burden may, for example, be disruptive to the metabolism of the producer cell. Such questions are pertinent in the laboratory and perhaps more importantly when scaled up for industrial production. Microcalorimetry has long been used to analyse quantitatively the growth and metabolism of microorganisms.

We suggest that such investigations may enjoy a renaissance in the biotechnological future of the pharmaceutical industry.

iii) As the major cause of human death and illness worldwide microorganisms are the focus of numerous existing therapeutic and preventative products with many more still required. The perpetual emergence of resistant microorganisms necessitates the perpetual search for new agents to counter them. The burgeoning fields of genomics and proteomics offer the possibility of specifically designing antimicrobial agents against a target organism . Conversely, the approach of high throughput screening requires the testing of thousands of chemical compounds against the target organism(s). Both of these approaches require the identification of effective candidates and an understanding of how they work. Microcalorimetry could be an important tool in this process: it offers a very sensitive, quantitative view of processes as they are happening. Conventional microbiological techniques offer none or very few of these advantages.

Interactions of drugs with their target(s) have also been explored by microcalorimetry, looking for synergic (increased efficacy) and antagonistic (competition for one binding site) actions that could shape the way in which combination therapies are administered. Minimal inhibitory concentrations of drugs can be easily obtained through calorimetry and a log dose response can be deduced, again shaping the way in which a drug is administered. Calorimetry can be used also to determine the efficacy of novel drug delivery systems because it is able to look at complete, heterogeneous systems in situ without the need for invasive sampling.

Microorganisms are the ideal biological model for microcalorimetry since they are discrete, self-perpetuating cells that are robust and, typically, grow under simple conditions.

Compared with other ...