In the early years of the last century, Paul Ehrlich coined the term “magic bullet” to indicate a therapeutic agent that targeted an infectious agent or tumor with exquisite specificity (Schwartz, 2004). He was inspired by his work with antibodies to imagine a future age of impressively discriminating and extremely effective drugs. Perhaps the class of therapeutic agents with the longest and most impressive record of illustrating this concept has been antibiotics. However, as a recent example (Kumarasamy et al., 2010) from the vast and continuously growing literature on antibiotic resistance illustrates, the ever-expanding list of evolving mechanisms through which bacteria counteract the actions of these therapeutic agents has put their continuing effectiveness in jeopardy.
Kumarasamy et al. show that isolates of the Gram-negative pathogens Escherichia coli and Klebsiella pneumoniae at sites in India and the United Kingdom express a relatively “new” beta–lactamase (New Delhi metallo- beta –lactamase 1, or NDM-1) that confers resistance to carbapenem antibiotics. Unfortunately, there are few antibiotics to turn to for the treatment of infections by Gram-negative bacteria resistant to carbapenems. Given the current relative lack of interest in development of antibiotics by major pharmaceutical companies (Payne et al., 2007), and the rapid spread of resistance mechanisms that affect many antibiotics, the authors suggest that in a decade or two we may face a serious lack of therapeutic options effective against Gram-negative pathogens.
It seems likely that patterns of antibiotic usage in medicine and agriculture are contributing to the evolution of multi-drug resistant bacterial strains through a process of what might be termed unnatural selection. This threatening process often involves bacterial species of minor or no medical significance that serve as sources of new genes encoding proteins that inactivate antibiotics. Thus, in working to meet the growing challenge of antibiotic resistance, an ecological and evolutionary perspective will be essential to maximizing our chances of averting future infectious disasters.
Schwartz, R. S. Paul Ehrlich’s magic bullets. N Engl J Med 2004; 350:1079-1080.
Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, Chaudhary U, Doumith M, Giske CG, Irfan S, Krishnan P, Kumar AV, Maharjan S,Mushtaq S, Noorie T, Paterson DL, Pearson A, Perry C, Pike R, Rao B, Ray U, Sarma JB, Sharma M, Sheridan E, Thirunarayan MA, Turton J, Upadhyay S, Warner M, Welfare W, Livermore DM, Woodford N. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis. 2010 Sep;10(9):597-602. Epub 2010 Aug10. PubMed PMID: 20705517; PubMed Central PMCID: PMC2933358.
Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov. 2007 Jan;6(1):29-40. Epub 2006 Dec 8. Review. PubMed PMID: 17159923.