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The Andres Lab: Probing DNA Damage Repair in Bacteria Using Structural Biology

Written by Beth Culp, PhD Candidate, Wright Lab

The Andres lab is interested in understanding the fundamental molecular mechanisms behind bacterial DNA damage response and repair pathways that contribute to microbial survival. They explore processes in biochemistry and structural and cellular biology to determine the unique and critical protein and nucleic acid components in these pathways, which can then be targeted to develop new therapeutic strategies for drug-resistant infections.

 

Dr. Andres favorite piece of equipment in her newly renovated laboratory space is the Art Robbins Instruments Crystal Gryphon (bottom) – an awesome liquid handling robot that lets her team screen a lot of crystallization space quickly and using minimal samples.

Developing new antibiotics begins with an in-depth understanding of the mechanisms of antimicrobial action and resistance. Dr. Sara Andres, member of the Institute for Infectious Disease Research (IIDR) and Assistant Professor in the Department of Biochemistry and Biomedical Sciences, along with her research team, aim to expand this foundational knowledge and apply it to antibiotic development by studying bacterial DNA damage repair.

The Andres lab addresses three main research questions: What are the molecular mechanisms of DNA repair in bacteria, what differences are there between bacterial species, and how can DNA repair be inhibited in order to improve antimicrobial therapies? In addition to antibiotics that directly cause DNA damage, including the clinically relevant fluoroquinolone class of DNA gyrase inhibitors, many antibiotics with diverse mechanisms may indirectly lead to DNA damage through the generation of free radical species. Inhibiting DNA repair may, therefore, provide a means to potentiate the activity of these antibiotics. Dr. Andres offers a strategic approach to studying these mechanisms by combining her expertise in structural biology with biochemistry and molecular biology techniques. Analyzing the involved enzymes and mechanisms with atomic resolution will allow for the design of inhibitors to these processes with important impacts on antimicrobial therapy.

Dr. Andres is one of the newest members of the IIDR, joining McMaster as a faculty member in August 2017. However, she is no stranger to McMaster, completing her PhD under Dr. Murray Junop in 2011 studying eukaryotic DNA repair using structural biology. Looking back, she remembers several turning points during her training when she discovered her passion for structural biology, with its mind-boggling ability to understand proteins at the atomic level. After solving her first crystal structure, Dr. Andres made the decision to transfer from a MSc to a PhD program, which she names as one of the best things she could have done. After completing her PhD, Dr. Andres moved to the National Institute of Environmental Health Sciences for post-doctoral training with Dr. Scott Williams where she studied a mechanism of DNA repair called homologous recombination and expanded her structural biology skillset to include small-angle x-ray scattering and atomic force microscopy.

Today, the Andres lab is small but mighty, comprised of MSc candidate Lucas Koechlin and a group of talented undergraduates, Amro ElRafie and Mitacs Globalink Intern Jose Rascon. They are primed for growth, welcoming more graduate students in September and recently moving into a larger, newly renovated lab space in MDCL in April 2019.

Just a few images of the beautiful crystal proteins and structures captured in the Andres Lab.

One of the major projects in the lab focuses on a DNA repair pathway known as non-homologous end joining (NHEJ). While NHEJ in eukaryotes is well understood, it was only discovered in bacteria in the early 2000s and remains only partially characterized. Unlike homologous recombination, NHEJ takes place in the absence of a second copy of homologous template DNA and occurs by identifying DNA double-strand breaks and haphazardly ligating them together. It is an important process for cells with a low metabolic activity that do not necessarily possess a second copy of their chromosome that is usually available in actively replicating bacteria. Of particular clinical importance, Mycobacterium tuberculosis is often found in a metabolically dormant state and in macrophages where they are subject to oxidative stress causing DNA damage. Therefore, targeting NHEJ in M. tuberculosis could help to clear latent infections. Efforts are currently focused on identifying the structural features of two key players in NHEJ, Ku and LigD, and their interactions with each other or with DNA.

When asked about the things that she enjoys most about being a principal investigator, Dr. Andres cites her freedom to research the questions that interest her most. Along these lines, the lab is also involved in a project supported by NSERC-Engage and in collaboration with Virox Technologies Inc., a leading industry partner in hydrogen peroxide-based disinfectants, to investigate the potential effects of the misuse of disinfectants on bacteria and their susceptibility.

With momentum building and Dr. Andres as their fearless leader, the Andres lab is an exciting place to be. She is often in the lab, mentoring in lab techniques or building new projects for future students. If not in the lab or her office, you can be directed as to where to find Dr. Andres by a clever chart on her door. Be sure to stop by to say hello, and especially if it is to chat about protein crystallography!

 

About the Author

 

Beth Culp, PhD Candidate

Beth joined Dr. Gerry Wright’s lab in 2015 after completing her undergraduate degree in Biology at McMaster University. Here, she is interested in discovering new antibiotics from soil bacteria. If she’s not in the lab, you’ll probably find her running, playing the trumpet, or eating chocolate.

 

Author:

Christy Groves