How will humanity deal with the pressing need for new drugs to treat bacterial and fungal pathogens that are resistant to antibiotics? How will society deal with new viral epidemics? The COVID-19 pandemic has made abundantly clear the threat of infectious diseases and our unpreparedness as a community. The MMG theme uses the vast amounts of genomic information available from diverse sources including bacteria, viruses, fungi, humans and birds to search for new molecular mechanisms to fight infectious diseases. The theme focuses on two main goals, development of new antibiotics and identification of effective antibody and peptide-based strategies against viruses.
Widespread overuse has led to a decline in the efficacy of current antibiotics, resulting in pathogens resistant to all commonly used compounds. Roughly 70 percent of current antibiotics, and more than half of all medicines, are derived from microbially produced natural products, or secondary metabolites — small molecules with unique, and often medically relevant, properties. Ample evidence suggests that a multitude of useful microbial natural products await discovery. A better way to exploit this potential is urgently needed.
The MMG research theme brings together a team of microbiologists, chemists, biochemists, and engineers to search microbial genomes for the ability to produce new metabolites. Our goal is to learn how these molecules are produced in microorganisms, to understand the enzymatic transformations responsible for their synthesis, and to understand their function and potential to either use them as drug candidates or inhibit their production as strategies to target pathogens. Researchers will create and use cutting-edge tools to:
- Identify processes through which bacteria utilize metabolites
- Discover new, medically relevant metabolites
- Predict the substrates and products of uncharacterized microbial enzymes
- Engineer microorganisms to cost-effectively produce new metabolites
- Modify these metabolites through synthetic chemistry or biology to improve their effectiveness
- Create unique, high-throughput screening methods to assess the metabolite’s efficacy and toxicity to pathogens
- Inhibit the production of metabolites that are essential for the survival of pathogens
Scientists will search for these answers by unlocking the vast genetic potential of microbial genomes using sequence-based and metabolomics-based approaches. This research may ultimately lead to the discovery of novel classes of antibiotics, improved production methods, and better ways to examine antibiotic efficacy in human and animal hosts. In addition, the information gleaned from these studies will improve our ability to annotate the function of genes, predict enzyme products, and understand enzymatic reactions.
Viruses present a unique challenge in the fight against infectious diseases owing to their high mutation rates, often high infectivity, and crossover potential from animals to humans and vice versa. The development of vaccines or neutralizing antibodies have proven effective and general strategies against viruses. However, identifying vaccines or antibodies against new pathogens can be time consuming and their effectiveness typically varies widely. In addition, the fast mutation rates of many viruses can limit the effective lifetime of antibodies or vaccines. MMG theme members are developing several strategies to improve preparedness for emerging viruses with high pandemic potential.
The theme brings together microbiologists, virologists, biochemists, chemists, and engineers to understand how organisms such as ducks can serve as reservoirs for certain viruses (avian influenza) without getting sick. Our goals are to learn how the antibody response of these organisms may protect them, to identify antibodies with high neutralizing ability, and to engineer antibodies to improve their effectiveness as potential human therapeutics. Researchers will create and use a number of tools to:
- Identify antibodies in ducks against avian influenza (bird flu)
- Understand the mechanism of duck antibody action
- Develop new methods to rapidly engineer, evolve and select for improved antibodies
- Investigate the ability of these antibodies to neutralize viruses
- Develop methods to engineer and evolve cyclic peptides and use them as antibody surrogates
Understanding how ducks protect themselves against bird flu may provide important information to prevent spillover of avian influenza to humans and livestock. This research may ultimately lead to the discovery of highly effective antibodies, identify epitopes for vaccine development, and new methods for evolution of antibodies and cyclic peptides.