The development of drugs that cure rather than prevent infections has had a major impact on human health. Antibiotics, which are either bactericidal (they kill bacteria) or bacteriostatic (they inhibit bacterial growth without killing), are the most successful class of such drugs. Penicillin was one of the first antibiotics = jumps from monkey and ape to human
Figure 23–31 Diversification of HIV-1, HIV-2, and related strains of SIV. HIV comprises different viral families, all descended from SIV (simian immunodeficiency virus). On three separate occasions, SIV was passed from a chimpanzee to a human, resulting in three HIV-1 groups: major (M), outlier (O), and non-M non-O (N). The HIV-1 M group is the most common and is primarily responsible for the global AIDS epidemic. On two separate occasions, SIV was passed from a sooty mangabey monkey to a human, resulting in the two HIV-2 groups. In 2009, a new strain of HIV was discovered that appears to have resulted from SIV passage from a gorilla to a human.
1292 Chapter 23: Pathogens and Infection
H2N2 H3N?
used to treat infections in humans, just in time to prevent tens of thousands of deaths from infected battlefield wounds in World War II. Because bacteria (see Figure 1–17) are not closely related evolutionarily to the eukaryotes they infect, much of their basic machinery for DNA replication and transcription, RNA translation, and metabolism differs from that of their host. These differences enable us to develop antibacterial drugs that exhibit selective toxicity, in that they specifically inhibit these processes in bacteria without disrupting them in the host. Most of the antibiotics that we use to treat bacterial infections are small molecules that inhibit macromolecular synthesis in bacteria by targeting bacterial enzymes that either are distinct from their eukaryotic counterparts or are involved in pathways such as cell wall biosynthesis that are absent in animals (Figure 23–33 and see Table 6–4).
However, bacteria continuously evolve and strains resistant to antibiotics rapidly develop, often within a few years of the introduction of a new drug. Similar drug resistance also arises rapidly when treating viral infections with antiviral drugs. The virus population in an HIV-infected person treated with the reverse transcriptase inhibitor AZT, for example, will acquire complete resistance to the drug within a few months. The current protocol for treatment of HIV infections involves the simultaneous use of three drugs, which helps to minimize the acquisition of resistance for any one of them.
There are three general strategies by which a pathogen can develop drug resistance: (1) it can alter the molecular target of the drug so that it is no longer sensitive to the drug; (2) it can produce an enzyme that modifies or destroys the drug; or (3) it can prevent the drug’s access to the drug target by, for example, actively pumping the drug out of the pathogen (Figure 23–34).
Once a pathogen has chanced upon an effective drug-resistance strategy, the newly acquired or mutated genes that confer the resistance are frequently spread throughout the pathogen population by horizontal gene transfer. They may even spread between pathogens of different species. The highly effective but expensive antibiotic vancomycin, for example, is used as a treatment of last resort for many severe, hospital-acquired, Gram-positive bacterial infections that are resistant to most other known antibiotics. Vancomycin prevents one step in bacterial cell wall synthesis—the cross-linking of peptidoglycan chains in the bacterial cell wall (see Figure 23–3B). Resistance can arise if the bacterium synthesizes a cell wall using different subunits that do not bind vancomycin. The most effective form of vancomycin resistance depends on the acquisition of a transposon (see Figure 5–60) containing seven genes, the products of which work together to sense the