Introduction: Drug Resistance

The evolutionary pressure of survival drives the emergence of drug resistance, and thereby poses a major challenge to modern medicine. Resistance threatens the longevity of drugs and restricts treatment options for patients, with high prevalence in all areas of oncology and infectious diseases. Any biological entity capable of evolving and creating diversity can develop resistance under selective pressure. This diversity can pre-exist or occur after exposure to the inhibitors. Pathogens evolve to resist antimicrobials, which include antibiotics, antivirals, antifungals and antiprotozoals. In agriculture, resistance arises with overuse of herbicides and pesticides. In cancer, resistance emerges eventually with most treatment regimens and in infectious diseases with spread of the pathogen to large populations, which is further exacerbated with the overuse of antibiotics. The emergence and spread of drug resistance in these wide range of disease areas severely impact public health, threaten millions of people’s lives, and cause a crippling financial burden, which urges the development of new strategies to unravel and avoid drug resistance.

Despite seemingly disparate, certain mechanisms have been uncovered repeatedly to be conferring drug resistance across quickly evolving diseases. On the molecular level, resistance is often associated with genetic changes such as site mutations, deletions, gene amplifications. Alternative resistance mechanisms involve decreasing the effective drug concentration or eliminating dependence of survival on the activity of the target. “Persister” cells that change phenotype to tolerate drugs might be promoting resistance in both antibiotics and cancer. Another common problem across diverse disease areas is inherent or acquired heterogeneity, especially for viruses and cancer cells, which can cause a certain fraction of the targeted variants to survive and drive disease progression and resistance. To thwart resistance it is necessary to elucidate the molecular mechanisms by which resistance occurs, identify vulnerabilities in current drugs, and use innovative integrated methods to design and discover novel therapeutics that are ideally less susceptible to resistance. In this effort applying lessons learned for one disease in the design of therapeutics to other diseases is essential. This issue of Chemical Reviews will hopefully foster connections between various fields around the theme of drug resistance, and inspire novel applications of ideas and discoveries. Common mechanisms and challenges in drug resistance necessitate a united front with a collective effort to leverage chemistry, while considering the constraints of evolution, to discover robust drugs or drug combinations that last and avoid resistance.

Historically, the challenge of drug resistance was realized initially in the treatment of HIV-1 infections where combination therapy, which involves inhibiting multiple targets with specifically designed direct acting antivirals, significantly reduced the viral burden of patients in the late 1990s. A decade later, combination therapy and other principles learned from HIV-1 were applied to successful treatment of hepatitis C infection. In the last 20 years many of these strategies were also translated to oncology, where academic research and the resources of pharmaceutical industry have made great strides, although treatment failure is still a common outcome due to resistance. Unfortunately, due in part to being less financially lucrative, progress in the development of potent novel drugs that avoid resistance for infectious diseases has lagged. Perhaps the current CoVID-19 pandemic caused by the SARS-CoV-2 virus and the subsequent response by the scientific community will translate into advancements in our drug design strategies against evolving infectious pathogens.

In this issue of Chemical Reviews on Drug Resistance a variety of techniques across scientific fields, including structural biology, medicinal chemistry, enzymology, computational chemistry, nanotechnology, systems biology and ethnobotany are applied to identify mechanisms of drug resistance and novel drug candidates. Structure-based drug design has been key in the discovery and optimization of direct acting antivirals. With insights from structure, viral evolution, and conformational dynamics of viral enzymes, the reviews by Schiffer and co-workers and Sarafianos and co-workers detail the molecular mechanisms of antiviral resistance and strategies to apply evolutionary constraints in antiviral design. These strategies include constraints such as restricting the inhibitor within the substrate envelope, and establishing interactions with the target protein’s evolutionary conserved features —the active site, backbone atoms, metal coordinating residues or allosteric sites— that can be engaged by inhibitors to avoid resistance. Such structure-based strategies are in principle generalizable to all disease targets, antiviral, antimicrobial or oncological, where target mutations confer resistance to current inhibitors.

Similar themes discovered regarding the molecular mechanisms of resistance for antivirals are also observed in oncology when the drug target mutates, along with a broad range of other cellular mechanisms. Smith and coworkers highlight the challenges of drug resistance in small molecule cancer therapeutics, reviewing 19 therapeutic targets with over 70 drugs often optimized with structure based strategies. They describe the approaches that have been taken to combat resistance, including to overcoming the blood brain barrier, combining small molecule drugs with biologics and designing covalent linkages to the target. The review by Goldman and co-workers takes on the challenge of overcoming drug resistance in oncology through novel biomedical engineering techniques. These range from mathematical models to simulate the underlying evolutionary principles by which resistance occurs; bioengineered tumor models of resistance that utilize microfluidics to test a variety of therapeutic strategies including combination therapies and these models become effective diagnostics; and therapeutics that involve nanotechnology to enhance selective drug delivery to avoid resistance. Even with targeted therapy and recent advances in immunotherapy, resistance persists as a major problem in cancer treatment, and such innovative and alternative approaches are much needed to better understand the underlying mechanisms of resistance and devise strategies for improved patient outcomes.

In addition to site mutations which is common in antiviral resistance, additional resistance mechanisms emerge in infections caused by fungus, bacteria or parasites. These include mechanisms involving cellular pathways as in cancer, which present additional challenges to the effectiveness of drugs.

In the treatment of fungal infections, which are eukaryotes, many analogous molecular machineries that exist in the host provide particular challenges. For the pathogenic candida species, described by Cowen and coworkers, only three classes of drugs exist, polyenes, azoles and echinocandins, all three of which are compromised by resistance. While mutation of the drug target is still common for all three classes, efflux pumps and target overexpression also subvert the azoles. Strategies to avoid resistance include combination therapies, targeting virulence factors and developing immunotherapies and vaccines.

Antibiotic resistance has been increasing at alarming rates with hardly any novel antibiotics in clinical development. Once a mainstay of antibiotics due to their ability to disrupt the bacterial cell wall, β-lactams have been severely compromised by resistance. As a case study against the prokaryotic gram-positive bacteria Staphylococcus aureus, Fisher and Mobashery describe the molecular mechanisms of β -lactam resistance. This class of antibiotics target a set of penicillin binding proteins, which are key enzymes in cell wall biosynthesis. Through elucidation of these enzymes and resistance, opportunities for novel antibiotics are likely.

Wright and co-workers view antibiotic resistance through what they describe as the antibiotic resistome, or the collection of all genetic elements that confer resistance. They focus on two classes of antibiotics, aminoglycosides and tetracyclines, and describe the machinery by which resistance occurs to each class. This systems approach enables understanding how efflux pumps, modifying enzymes and target modifications alter the effectiveness of antibiotics. These mechanisms not only permit bacteria from subverting therapeutics but are also mechanisms by which bacteria compete with and protect themselves from each other. They propose a model of resistance-guided antibiotic discovery leveraging the bacterial synthetic machinery.

Another rich source of possible antibiotics that should be less susceptible to resistance is described by Quave and co-workers as plant-derived natural products. Co-evolution of plants in bacterially rich environments has resulted in many metabolites with natural antibacterial activity often through interfering with virulence factors. In this comprehensive review, 459 such recently described plant natural products are assessed for their antibacterial activity (183 in detail). These plant-derived compounds fit within four main chemical classes (phenolic derivatives, terpenoids, alkaloids, and other metabolites) with many unique chemical scaffolds and many with quite potent antibacterial activities. Leveraging how plants evolved resistance to bacterial infections and potentially other infectious diseases is a promising pipeline for discovering new chemical entities for therapeutic development.

Overall in combating drug resistance we need to understand what happens at the molecular level, i.e. how evolution enables survival under drug pressure. By learning the constraints of evolution, we can leverage these requirements for enzymes to function in robust inhibitor design, the strategies fungi, bacteria and plants use to avoid each other’s virulence, and the involvement of our own host factors in infections or the growth of cancer. Agriculture avoids resistance, in part, by rotating crops and keeping down the stressors. In medicine sub-optimal drugs might be the stressors that drive resistance. However even with the best possible drugs, we may not be able to completely avoid resistance. Evolution is relentless. Instead we need a combination of approaches to curb evolution the best we can. Through an integrated understanding of chemical and biological entities and their impact on our own microbiome, virome and metabalome we can help strengthen innate and adaptive immune system to work in complementing drugs to decrease probability of resistance. To counter resistance, strategies must become less reactionary and rather more integrated, preemptive and robust.

ACKNOWLEDGEMENTS

Biographies

Footnotes