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Pharmacogenomics—Is There a Role in Antibiotic Therapy?

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Pharmacogenomics—Is There a Role in Antibiotic Therapy? Pharmacogenomics—a role in antibiotic therapy? DB Davison et al 14 sist over long periods of time, and they there are inborn cohesive forces 1 Pinker S. How the Mind Works. WW Nor- cannot grow except by recruitment. which cause the different individ- ton & Company: New York, London, 1997, pp 1–528. In short, populations differ from uals within a population to coop- 2 Wynne Edwards WC. Evolution through each other because many of their erate sufficiently for the popu- group selection. Blackwell: Oxford, 1986. members tend to carry different lation to function as one 3 Wilson DS. Proc Nat Acad Sci USA 1975; 72: mutants; furthermore, it is the non- evolutionary unit. 143–146. 4 Wilson DS. Science 1997; 276: 1816–1817. uniformity of the individual members (2) As a second requirement, there 5 Wilson DS, Sober E. J Theor Biol 1989; 136: of a population which helps a popu- must be effective evolutionary dif- 337–356. lation to function as an effective ferences between individuals 6 Rice SH. J Theor Biol 1995; 177: 237–245. entity, and thereby to allow evolution- which at the same time make 7 Crognier E. Ann Hum Biol 2000; 27: 221– 237. ary competition. The situation is anal- every population different from 8 Michod RE, Roze D. Heredity 2001; 86:1–7. ogous to that of a complex organism other populations. The existence 9 Hamilton WD. J Theor Biol 1964; 7:1–52. which has different cells, but they col- of mutations assures the occur- 10 Maynard Smith J. Evolutionary Genetics (2nd laborate and form a living unit. Many rence of differences between indi- edn). Oxford University Press: Oxford, New York, Tokyo, 1998, pp 163–178. of the individual diversities in a popu- viduals as well as between popu- 11 Bradley BJ. Q Rev Biol 1999; 74: 171–194. lation are genetically controlled, as are lations. 12 Chomsky N. Chomsky’s Classic Works. Lang- the different cells of a multicellular uage and Responsibility and Reflections on Important in the current context is organism. Language. New Press: New York, 1998. the fact that it is genetic factors carried 13 Pinker S. Nature 1997; 387: 547–548. To allow evolutionary forces to by individuals which make it possible 14 Lorenz K. Evolution and Modification of favor, or to eliminate, either an indi- for populations to function as differ- Behavior. University of Chicago Press: vidual or a population, there are two Chicago, IL, 1971. ent evolutionary units. requirements applying to both these 15 Charrier I et al. Nature 2001; 412: 873. 16 Weimerskirch H et al. Nature 2001; 413: units of selection: DUALITY OF INTEREST 697–698. 292 (1) The first requirement is the pres- None declared. 17 Goldenberg J et al. Science 2001; : 2433. ence and function of cohesive 18 Seashore CE. Psychology of Music. Dover: Correspondence should be sent to forces; we are not surprised when New York, 1967. W Kalow, Department of Pharmacology, the cohesive forces between the 19 Boehm C. Curr Anthropol 1993; 34: 227– Medical Sciences Building, University of different cells of a multicellular 254. Toronto, Toronto M5S 1A8, Canada. 20 Kalow W. Pharmacogenetics 2001; 10:1–3. organism allow this organism to Tel: 416 978 2734 21 Siller S. Nature 2001; 411: 689–692. act as an individual. However, we Fax: 416 978 6395 also have to accept the fact that Email: w.kalowȰutoronto.ca of predictable outcomes from a study Pharmacogenomics—Is there a role of human genomes and their responses ex vivo to a particular phar- in antibiotic therapy? macological agent.2,3 Treatment of infectious diseases is a DB Davison1, TJ Dougherty2, JF Barrett3 and M Pucci1 bit of a therapeutic outlier. Ideally, one desires an agent that has no discern- 1Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, USA; 2Pfizer ible effects on the host of an infection, Global Research & Development, Groton, CT, USA; 3Merck Research Laboratories, while having lethal effects on the Rahway, NJ, USA invading organism. Neither of these ideals is ever achieved. When one thinks of pharmacogenomics in infec- The Pharmacogenomics Journal (2002) 2, and possibly adverse events that vary tious diseases, it is often in the context 14–16. DOI: 10.1038/sj/tpj/6500064 with the host’s repertoire of gene poly- of drug effects (P450 interactions, etc) 1 morphisms. Several of the most obvi- and seldom in terms of the microbial In its purest form, pharmacogenomics ous and well-discussed areas of pharm- population that the drug affects. Usu- is defined as the functional linkage of acogenomics potential have been ally this is couched in terms of a the science of human pharmacology, oncology, CNS disorders, and decision in prescribing of a drug to toxicology and genomics. This link is inflammation, where a pattern of gene which the patient may be allergic or somewhat artificial, and in its current expression (up- or down-regulation) prescribing a drug to which the patient usage, pharmacogenomics implies an may be monitored in response to a may have an adverse response due to association of some pharmacological given pharmacological agent. The ulti- aberrant metabolism because of, eg, agent with measurable host responses mate promise of pharmacogenomics is polymorphic variations in the The Pharmacogenomics Journal Pharmacogenomics—a role in antibiotic therapy? DB Davison et al 15 expression of the repertoire of human organisms. It has become clear that Another important pharmacogen- cytochromes. If a pharmacogenetic, or microbial populations, despite being omic measurement is the pathogen’s pharmacogenomic evaluation was largely clonal at the onset, can during response to both the host immune somehow instantaneously possible, an infection become heterogeneous in response and the antibiotic used to the drug of choice would be matched terms of, for example, antibiotic resist- suppress or kill it. The host response against the maximum compatibility of ance. Let’s consider the possible exam- can be assessed by its ability to invoke the host and maximal effect on the ination of antibiotic resistance by a a competent host immune response, infectious agent. pharmacogenomics analysis. There is both non-specific(ieRESsystem)and However, there may not be any evidence accumulating that differing specific (antibody or T-cell response). more significant effector of human environments (eg, in a host Gene markers can quantitatively pharmacology than the microbial compartment) and stress (eg, anti- measure all of these responses, but infection itself (bacterial, fungal and biotic treatment) can increase none at present immediately help viral). The cascade of gene expression mutation rates in bacteria.6 This popu- with diagnosis of infection or choice response to infection is diverse and lation heterogeneity, in turn, can lead of therapy. immense, affecting numerous human to increased rates of resistance devel- The bacterium’s response at the gen- host response genes including the opment and treatment failures. This omic level, however, may be a very complement cascade, general heterogeneity of bacterial populations direct and quick indicator of the resist- inflammation responses, febrile in an infection can become quite ance potential. For example, the response, the numerous immune marked; for example, a very high per- science of gene expression profiling response systems, and likely additional centage of mutators are found among (microarrays, etc) has evolved to the factors yet to be uncovered. The Pseudomonas aeruginosa isolated from point that, within a day or two, a com- human population heterogeneity can cystic fibrosis patients.7 plete time-sequence-based expression have an even more profound influence The predictive nature of data from a pattern of gene products could be on the outcome of infection. Con- pharmacogenomic evaluation of any assessed in bacteria. This would allow sider, for example, the presence of sin- given drug’s effects on a pathogen for contrasting the ‘normal’ and ‘drug gle-nucleotide polymorphisms in the could have a significantly greater affected’ bacterium to see what effects human population; these minor differ- impact than single point MIC drug treatment may have on the ences in certain genes are known to measurements. That is, a MIC deter- dynamics of the pathogen population. affect the outcome of the events asso- mines the ability of a drug to inhibit The ability of chips to detect single ciated with the gene products. A visible bacterial growth in a standard mismatches and expression levels of recent, well-publicized example is that assay, but does nothing to predict key resistance genes could be used of individuals naturally resistant to resistance potential, mode of inhi- both to detect resistance mutations, HIV.4 A mutation in the CD4 receptor bition (bactericidal or bacteristatic), and measure expression levels of resist- prevents the virus from binding, thus virulence, efflux, genes turned on or ance genes. If a profile of relevant preventing infection. Another off—all ‘genomics-measurable’ para- example is the recent discovery of meters that may better predict the out- mouse polymorphisms in the kif1C come of a given treatment regimen. gene that alter susceptibility of macro- But how could this work? The most phages to anthrax toxin.5 It is antici- straightforward way to proceed would pated that this genetic basis for be a ‘profiling’ of gene expression in anthrax susceptibility will extend to devising a pharmacogenomic evalu- man. The antimicrobials used to treat ation, most likely established initially pathogens may also affect the ‘pharm- by whole genome microarrays with a acogenomic’ response in humans significant contribution possible from indirectly by affecting the presen- proteomics. Effects normalized to tation of a pathogen to the human drug-free controls and normalization host (eg modification of the pathogen to growth rates of a pathogen may pro- surface or lytic events exposing bac- vide data in which a rapid diagnostic terial intracellular content).
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