The modern era of antimicrobial therapy is ~60 years old. It has produced agents that target bacterial cell wall biosynthesis (e.g., penicillins, cephalosporins, vancomycin, Isoniazid), protein synthesis (e.g., aminoglycosides, tetracyclines, chloramphenicol, oxazolidinones, macrolides), RNA synthesis (e.g., rifampin), and DNA metabolism (e.g., sulfonamides, quinolones). Despite this diversity of targets, resistance remains a universal accompaniment to antimicrobial therapy. Microbes use remarkably diverse strategies to overcome selective pressure, and much is known about the mechanisms of antimicrobial resistance. Although antimicrobial resistance remains a major problem on a population level, the emergence of drug resistance in an individual patient with a chronic infection can be prevented by the administration of a highly effective combination therapy regimen, which either cures the patient or prevents death from previously lethal infections.
The history of targeted cancer therapy is much shorter than that of infectious diseases, but already it is replete with a similarly diverse range of resistance mechanisms. However, effective combinations leading to cures have not yet emerged. Oncology has a track record of prior success in developing curative combination chemotherapy for pediatric leukemia, germ cell tumors, and lymphoma, but this progress required decades of empirically mixing and matching available agents. There is optimism that this timeline can be shortened with targeted cancer drugs because our understanding of cancer biology today is markedly more advanced.
Here we compare and contrast examples of drug resistance in infectious diseases and cancer, with the hope that lessons learned in one field may inform the other. We acknowledge that this is a forced comparison. There are fundamental differences in the principles underlying the search for drugs that target a foreign invader (i.e., in infections) versus mutant cells that emerge from the host (i.e., in cancer), particularly with regard to anticipated toxicities. Yet, current drug-targeting strategies in both fields share the goal of exploiting the unique dependencies of each disease, such as tumor-specific mutations in cancers or microbe/virus-specific targets in infectious agents. Another challenge in comparing these disciplines are the different definitions of treatment success. Resolution of the illness in the patient is central to both, but the infectious diseases field must also consider the impact of drug resistance on public health. Overtreatment with broad spectrum antibiotics cures most patients but hastens the emergence and spread of multi-drug-resistant strains, which can impact the health of currently uninfected individuals.
Rather than divide the discussion into separate sections on infectious diseases and cancer, we consider both fields together, beginning with mutational and nonmutational mechanisms of resistance (). We follow with a review of successful combination drug strategies in infectious diseases. We provide insights into why they worked and highlight a few instances when monotherapy is surprisingly effective in both disciplines. We conclude with the argument that molecular diagnostics, which already play a critical role in defining drug-sensitive subsets of cancer patients, could also transform current infectious diseases treatment. To learn more about the mechanistic details of and treatment options for drug resistance in HIV, tuberculosis (TB), and malaria, see Review by Goldberg et al. on page 1271 of this issue.