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Has man lost the battle against infectious disease?

It is often said that humans are losing the battle against disease. I disagree. Our opportunities are ongoing, progress continues, and we are winning the battle. The efforts of human to control infection have a long history, though in the past they were often ineffective. Early efforts control the plague failed, because they were based on the flawed belief that it was caused by a ‘bad air’ or miasma, rather than recognising that it was caused by an infectious agent transmitted by fleas carried by rats. However, after the acceptance of the germ-theory of disease, many effective interventions were developed. Lister’s use of carbonic acid to reduce infections during surgery set a precedent for the sterilization of surgical theatres and instruments, which has undoubtably saved countless lives.

There are many cases in which epidemics have been ended by careful interventions, such as cleaning water in areas where water-bourne infections are occurring (however, the popular belief that John Snow ended London’s 1854 cholera epidemic by disabling the Broad street pump is false; the epidemic was already drawing to a close). Other infections have been only partially controlled: no ‘treatment’ has been developed for HIV/AIDS, but Anti-Retroviral Therapy can extend life (and reduce infectiousness), Post-Exposure Prophylaxis can help prevent those exposed to HIV by needle-stick injuries from developing the disease, and the latex condom provides an effective barrier to its transmission via sexual intercourse.

More remarkably, some diseases (most notably smallpox) have been completely eradicated due to vaccination programs. Unfortunately, such programs are not universally successful: efforts to produce a effacious vaccine against HIV/AIDs have thus far failed; efforts to eradicate polio have stalled, and whilst it has been removed from most countries, there are still a few in which it remains stubbornly endemic. Public concern about vaccine safety hinder such programs—these concerns often lack a solid evidential basis, and occur not only in Africa, but also in the UK, as illustrated by the media hype surrounding Andrew Wakefield’s suggestion that the MMR vaccine could cause autism.

Alexander Fleming’s discovery of penicillin’s antibiotic effect (and the subsequent work of Florey and Chain) led to the first effective chemotherapeutic treatment for those suffering from bacterial disease. The class of antibiotics that includes penicillin (the beta-lactams) now has dozens of members, and many other classes have been developed. Unfortunately, the over-use of antibiotics imposed a selection pressure that led to the development of resistance in many organisms. There are many mechanisms by which resistance may occur, including production of enzymes that metabolize the antibiotic (such as beta-lactamases, which break open the beta-lactam ring), and pumps that remove them from bacterial cells. This is particularly concerning given the facility with which bacteria can exchange genetic material. At present, the most prevalent diseases caused by drug-resistant pathogens are multi-drug-resistant tuberculosis and Methicillin Resistance Stapylococcus Aureas (MRSA). A study, published last year in the journal Science, found that many common soil bacteria were able not only to survive at high concentrations of antibiotics, but also to use them as a nutrient-source1. As many of these bacteria are similar to pathogens, this is highly concerning. Nonetheless, there has been progress: it has been shown that using two beta-lactams in combination can be effective in killing drug-resistant-TB2: one of the beta-lactams is broken down very slowly, and effectively acts as a beta-lactamase inhibitor. Conveniently, both drugs are already in use, avoiding both regulatory hurdles in the licensing process, and difficulties in synthesis scale-up.

As antibiotic resistance has increased, development of new antibiotic classes has slowed. This is due partly to the fact that low-hanging fruit has been exhausted, and there are few easy targets remaining for new drugs to hit. There are also economic reasons: only a single course of antibiotics is prescribed at a time, but whilst a patient is put on some other types of drug (eg. statins) they will likely continue taking it for the rest of their lives. For these two reasons, antibiotic development is expensive, and does not result in high revenues. Nonetheless, there has been some progress: two new drugs with the potential for use as anti-tuberculosis agents have been recently described in the literature: one, a imidazole, acts by causing the formation of NO. This occurs only in infected cells, avoiding damage to healthy host cells, as it is dependent on an enzyme produced by the TB pathogen3

However, there is increasing awareness that drugs need not actually kill pathogens in order to cure a patient: rather, it may be sufficient to the expression of virulence factors. A recent paper in Science described a drug that prevented cholera bacteria from producing cholera toxin, and thus also from causing symptoms. At the same time, pilus formation was impaired, hindering entrance to cells of the intestinal epithelium. As the bacterium is not being killed by the drug, there is likely to be a weaker pressure driving selection for resistance. Similar approaches may be found to be useful against other pathogens4

In future, administering antibodies may have a greater role in treating infection. The approach was pioneered by Pasteur, who used transplants of blood form a succession of animals (including a rabbit and a horse) to treat a boy who had been infected with rabies by a dog-bite. As it is harder to demonstrate the indistinguishability of two complex proteins than it would be for a conventional small-molecule medicine, there is a higher regulatory barrier to the production of ‘generic’ biologics. The manufacturer of a biologic therapeutic agent may thus enjoy a monopoly maintained not only by intellectual property law, but also regulatory & safety law, making the development of biologics commercially appealing . Antibodies are used to treat some diseases (the most widely known is probably Hercepetin, which is used in some cases of breast cancer). In the last few months, researchers have been able to produce a modified version of Herceptin with affinity for a second antigen: this is the first example of antibodies with high affinities for two different biomolecules5. A team at Scripps research institute have produced an antibody that binds to the ‘tail’ of one of influenza’s surface proteins (hemagglutinin), a region which mutates more slowly that the ‘head’6. This targeting of a more stable epitope could allow the development of ‘flu vaccines that do not have to be re-formulated every-year as the result of epitope mutation/serotypic-shift. It could also, perhaps, allow the stockpiling of antibodies that could be administered directly to infected persons.

Surprisingly, gene therapy may be useful in treating not only genetic, but also infectious, diseases. The entry of HIV into white-blood cells is facilitated by a protein (CCR5) on its surface. A mutation (Delta-32) in this protein prevents HIV form binding to it, hindering infection. It was found that after a bone marrow transplant from a donor with the mutation, the recipient was able to come off anti-retrovirals, and has not since suffered viral rebound (the case was reported in the New England Journal of Medicine7. This is a promising result, but bone-marrow transplant procedures have an high morbidity and mortality. It would thus be desirable to bring about the change in blood-cell phenotype by gene therapy instead.

In conclusion, drug resistance is an increasing problem, and some vaccination programs have stalled (polio), whilst others have failed to get off the ground (HIV). However, there are now cures for many disease that were previously incurable, and new developments continue to be made. Many of these provide entire new paradigms for treatment, such as gene therapy (for HIV), carefully designed antibodies (for ‘flu), cleverer combination therapies (for TB), and inhibition of virulence factor formation (for cholera). Clearly, the battle is not lost—it still continues.

  1. Dantas et al. Bacteria subsisting on antibiotics. Science (2008) vol. 320 (5872) pp. 100-3 doi:10.1126/science.1155157

  2. Hugonnet et al. Meropenem-Clavulanate Is Effective Against Extensively Drug-Resistant Mycobacterium tuberculosis. Science (2009) vol. 323 (5918) pp. 1215 doi:10.1126/science.1167498

  3. Singh et al. PA-824 Kills Nonreplicating Mycobacterium tuberculosis by Intracellular NO Release. Science (2008) vol. 322 (5906) pp. 1392. doi:10.1126/science.1164571

  4. Hung et al. Small-Molecule Inhibitor of Vibrio cholerae Virulence and Intestinal Colonization. Science (2005) vol. 310 (5748) pp. 670 10.1126/science.1116739

  5. Bostrom et al. Variants of the Antibody Herceptin That Interact with HER2 and VEGF at the Antigen Binding Site. Science (2009) vol. 323 (5921) pp. 1610 doi:10.1126/science.1165480

  6. Ekiert et al. Antibody Recognition of a Highly Conserved Influenza Virus Epitope. Science (2009) vol. 324 (5924) pp. 246 doi:10.1126/science.1171491

  7. Hutter et al. Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation. The New England Journal of Medicine (2009) vol. 360 (7) pp. 692 doi:10.1056/NEJMoa0802905

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