Yonatan Grad lab

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This week we profile a recent publication in Nature Microbiology from the lab of Dr. Yonatan Grad (pictured, back left) at Harvard and Brigham and Women’s Hospital with first author Dr. Daniel Rubin.

Can you provide a brief overview of your lab’s current research focus?

We study how pathogens evolve and spread, from microbial genetics through epidemic dynamics, with goals of advancing clinical and public health practices. One major area of research is on the bacterial pathogen, Neisseria gonorrhoeae, which causes the sexually transmitted disease gonorrhea, because it is one of the most common bacterial pathogens (nearly 700,000 reported cases a year in the US) and because of its extensive antibiotic resistance.

What is the significance of the findings in this publication?

Antibiotic resistance is a growing problem, but even within a bacterial species there are some lineages that remain antibiotic susceptible. What explains why some lineages do not acquire resistance as readily? A developing area of study suggests that genetic factors that impact metabolism play a key role. In this paper, we make two important contributions to this field through our work on Neisseria gonorrhoeae.

First, we correct a longstanding misapprehension about N. gonorrhoeae biology and define the genetic basis of a fundamental metabolic trait that divides N. gonorrhoeae into two populations. While textbooks report and many microbiologists—including those who study the gonococcus—believe that culturing N. gonorrhoeae requires supplemental carbon dioxide, in fact many clinical isolates do not. We use a combination of genome-wide association methods and experimental work to show that this requirement is attributable to a single amino acid variant in beta carbonic anhydrase (CanB19EG), that CanB19G is a hypomorph, and that CanB19G is an innovation in N. gonorrhoeae compared to the other Neisseria. Second, we show that this variant in beta carbonic anhydrase influences acquisition of antibiotic resistance in vitro and in clinical populations. Analysis of clinical populations that include both genome sequences and antibiotic susceptibility data shows that CanB19G is associated with ciprofloxacin resistance, and experimental results demonstrate that strains with this variant that acquire resistance to ciprofloxacin compete equally with the parental susceptible strain, whereas those with CanB19E that acquire ciprofloxacin resistance suffer a fitness cost.

What are the next steps for this research?

How the intersection between metabolism, the environmental conditions in sites of infection, and genetic variation shapes the likelihood of acquisition and maintenance of antibiotic resistance is poorly understood. Developing tools to systematically explore this space could be useful for guiding development of new therapies and treatment strategies.

If you’d like to mention your funding sources, please list them.

Smith Family Foundation and NIAID / NIH.

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