Mechanisms of Antimicrobial Resistance

Spring 2019 Syllabus

Course Days/Hours: 2pm-4pm on April 1, 2, 3, 8, 9, 10, 15, 16, 17

Location: Genentech Hall S202

Instructors: James Fraser

Course Description:

This mini-course will be a survey of recent and classic papers on antibiotic resistance with an emphasis on evolutionary biology, biochemical mechanisms, and new ideas for chemical matter.

Course structure

Each students will serve as Discussion Leaders (pre-assigned below) for one paper topic. Everyone should be prepared for class by having read the paper carefully. The Discussion Leader will prepare a talk similar in content and quality to a Tetrad or QBC Journal Club presentation, with an estimated 30-40 minute duration (noting that interruptions and discussion may take us closer to an hour).

Introductory Lectures:

• April 2nd Danica Fujimori
  • RNA methylation by Radical SAM enzymes RlmN and Cfr proceeds via methylene transfer and hydride shift
  • RlmN and Cfr are Radical SAM Enzymes Involved in Methylation of Ribosomal RNA
  • Covalent Intermediate in the Catalytic Mechanism of the Radical S-Adenosyl-l-methionine Methyl Synthase RlmN Trapped by Mutagenesis
  • miCLIP-MaPseq, a Substrate Identification Approach for Radical SAM RNA Methylating Enzymes
• April 3rd Ian Seiple
  • A platform for the discovery of new macrolide antibiotics.
  • The evolving role of chemical synthesis in antibacterial drug discovery.

Good Introductory Resources:

• SnapShot: Antibiotic Resistance
• Lecture by Gerald Wright
• Molecular mechanisms of antibiotic resistance
• Assessing evolutionary risks of resistance for new antimicrobial therapies
• A Mysterious Infection, Spanning the Globe in a Climate of Secrecy

Industry retrospectives on antibiotic development

• GSK Drugs for bad bugs: confronting the challenges of antibacterial discovery
• AZ ESKAPEing the labyrinth of antibacterial discovery

April 8

• Leader: Haley Gause
• Assigned Paper: Antibiotic collateral sensitivity is contingent on the repeatability of evolution

• Additional/Alternate reading:: Darwinian Evolution Can Follow Only Very Few Mutational Paths to Fitter Proteins

• Leader: Joel Finbloom
• Assigned Paper: Spatiotemporal microbial evolution on antibiotic landscapes
• Additional/Alternate reading:: Genetic variation of a bacterial pathogen within individuals with cystic fibrosis provides a record of selective pressures.

April 9

• Leader: Bryan Faust
• Assigned Paper: Heterogeneity in efflux pump expression predisposes antibiotic-resistant cells to mutation

• Additional/Alternate reading::Antibiotic That Inhibits the ATPase Activity of an ATP-Binding Cassette Transporter by Binding to a Remote Extracellular Site.

• Leader: Natasha Puri
• Assigned Paper: Bactericidal Antibiotics Induce Toxic Metabolic Perturbations that Lead to Cellular Damage.
• Additional/Alternate reading: Oxidation of dCTP contributes to antibiotic lethality in stationary-phase mycobacteria

April 10 - start at 3PM

• Leader: Matt Nalley
• Assigned Paper: High mutation rates limit evolutionary adaptation in Escherichia coli
• Additional/Alternate reading: Identifying and exploiting genes that potentiate the evolution of antibiotic resistance

April 15

• Leader: Hayarpi Torosyan
• Assigned Paper: Inhibiting the Evolution of Antibiotic Resistance

• Additional/Alternate reading: Transposase-DNA Complex Structures Reveal Mechanisms for Conjugative Transposition of Antibiotic Resistance, This Week in Evolution

• Leader: Arthur Tran
• Assigned Paper: Optimized arylomycins are a new class of Gram-negative antibiotics
• Additional/Alternate reading: A new class of synthetic retinoid antibiotics effective against bacterial persisters

April 16

• Leader: Miriam Goldmon
• Assigned Paper: Prediction of ultra-high-order antibiotic combinations based on pairwise interactions

• Additional/Alternate reading: Drug combinations: a strategy to extend the life of antibiotics in the 21st century, Alternating antibiotic treatments constrain evolutionary paths to multidrug resistance., Accelerated evolution of resistance in multidrug environments.

• Leader: Katarina Pance
• Assigned Paper: Thermal proteome profiling in bacteria: probing protein state in vivo
• Additional/Alternate reading: Thermal proteome profiling: unbiased assessment of protein state through heat-induced stability changes. Species-specific activity of antibacterial drug combinations.

April 17 - start at 3PM

• Leader: Evelyn Hernandez
• Assigned Paper: Resource misallocation as a mediator of fitness costs in antibiotic resistance.
• Additional/Alternate reading: Antibiotic resistance and host immune evasion in Staphylococcus aureus mediated by a metabolic adaptation

if you don’t like your paper, maybe one of these would be more fun?

• Invertible promoters mediate bacterial phase variation, antibiotic resistance, and host adaptation in the gut
• Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection.
• Gamblers: An Antibiotic-Induced Evolvable Cell Subpopulation Differentiated by Reactive-Oxygen-Induced General Stress Response
• The evolution of substrate discrimination in macrolide antibiotic resistance enzymes.