Photo : Penn State University
My research aims to understand how microbial species interactions can be harnessed to minimize the evolution of harmful pathogen traits like virulence and drug resistance, which frequently undermine our most sophisticated medical interventions. My work combines experimental evolution, disease ecology, microbiology, and molecular biology and encompasses bacterial, viral, and trematode pathogens of a wide range of host taxa. Please see below a quick overview of my research projects.
Ongoing Research
1. Exceptions to the rule: Why does resistance evolution not undermine antibiotic therapy in all bacterial infections?
[Bhattacharya, Aluquin & Kennedy, Submitted]
Antibiotic resistance poses one of the greatest public health challenges of the 21st century. Yet not all pathogens are equally affected by resistance evolution. Why? . We document the observed prevalence of antibiotic resistance for ‘pathogen x drug’ combinations across 57 different human bacterial pathogens and 53 antibiotics from 15 drug classes used to treat them. Using AIC-based model selection we analyze 14 different traits of bacteria and antibiotics that are believed to be important in resistance evolution. Our results show that nosocomial pathogens and indirectly transmitted pathogens are significantly associated with increased prevalence of resistance whereas zoonotic pathogens, specifically those with wild animal reservoirs, are associated with reduced prevalence of resistance. We found partial support for high resistance evolution in gram positive and gram unclassified pathogens, pathogens with human microbiome reservoirs, pathogens with horizontal gene transfer, and pathogens with documented human-to human transfer. Surprisingly, global drug use, time since drug discovery, mechanism of drug action, and pathogens with environmental reservoirs did not emerge as statistically robust predictors of drug resistance evolution in our analyses. To the best of our knowledge this work is the first systematic analysis of resistance evolution across such a wide range of human bacterial pathogens, encompassing the vast majority of common bacterial pathogens. Insights from our study may help guide public health policies and future studies on resistance control.
2. Why is vaccine resistance less common than drug resistance?
[-with David A Kennedy, Penn State]
In this work, I am developing a powerful, new C elegans - Orsay virus study system to investigate how timing of intervention and multiplicity of targets affect the evolution of resistance against drugs and vaccines. For this work I am developing candidate antivirals as well as RNAi-based “vaccine-like” interventions to examine resistance evolution against these interventions. Stay tuned for results!!!
Previous Research
1. How do bacterial social interactions affect virulence evolution? Bacteria exhibit a wide array of social interactions ranging from mutual-benefit and cooperation to competition and spite. In fact, almost all known lineages of bacteria produce costly anti-competitor toxins called bacteriocins that can kill closely related competitor strains while sparing clone-mates of the producers. Bacteriocin production is considered ‘spiteful’ due to the direct fitness costs to both the producers and target competitors. My doctoral research investigated how bacteriocin-mediated competition can be harnessed to limit harmful pathogen evolution. My work provided the first direct evolutionary link between virulence and spite in bacteria (Figure 1) by demonstrating that the evolution of increased virulence is associated with the evolution of reduced bacteriocin production in the insect-pathogenic bacteria Xenorhabdus spp [Bhattacharya et al 2019, Biology Letters]. This work motivates the testable hypothesis that maintaining selection for bacteriocin-production during therapy may constrain virulence evolution.
2. Investigating how bacterial interspecific competition can be harnessed to decelerate drug resistance evolution. Rapidly spreading antibiotic resistance has led to the need for novel alternatives and sustainable strategies for antimicrobial use. Bacteriocins are a class of proteinaceous anti-competitor toxins under consideration as novel therapeutic agents. As part of my doctroal research, I examined how bacterial competition may be utilized to decelerate the evolution of bacteriocin resistance . We showed that incorporating live heterospecific competitors in conjunction with antimicrobials (specfically bacteriocins) could limit the evolution of antimicrobial resistance by competitively suppressing drug resistant variants [Bhattacharya et al, 2019, Evolutionary Applications]. This work demonstrated a powerful new, non-pharmacological approach to slow down the evolution of drug resistance.
3. How is "spite" maintained in bacterial populations? Bacteriocins are costly anticompetitor toxins ubiquitously produced across the bacterial kingdom that kill closely related competitor strains but do not kill clonemates of the producer cells. However, bacteriocin production is energetically costly, and deemed a 'suicide' mission as producer cells often must lyse to release these large proteinaceous toxins. Owing to direct fitness costs on both producers and target competitors, bacteriocin production is considered "spiteful". In fact, it is a rare example of spite in nature. How is such a costly trait maintained by selection? I investigated key theoretical predictions about the role of phenotypic plasticity in maintaining this costly trait in natural isolates of the insect-pathogenic bacteria, Xenorhabdus spp. We found that costly bacteriocins are produced even in the absence of target competitors, thus challenging the conventional assumption that bacteriocin production is a ‘suicide mission’ [Bhattacharya et al 2018, Ecology and Evolution].
1. Exceptions to the rule: Why does resistance evolution not undermine antibiotic therapy in all bacterial infections?
[Bhattacharya, Aluquin & Kennedy, Submitted]
Antibiotic resistance poses one of the greatest public health challenges of the 21st century. Yet not all pathogens are equally affected by resistance evolution. Why? . We document the observed prevalence of antibiotic resistance for ‘pathogen x drug’ combinations across 57 different human bacterial pathogens and 53 antibiotics from 15 drug classes used to treat them. Using AIC-based model selection we analyze 14 different traits of bacteria and antibiotics that are believed to be important in resistance evolution. Our results show that nosocomial pathogens and indirectly transmitted pathogens are significantly associated with increased prevalence of resistance whereas zoonotic pathogens, specifically those with wild animal reservoirs, are associated with reduced prevalence of resistance. We found partial support for high resistance evolution in gram positive and gram unclassified pathogens, pathogens with human microbiome reservoirs, pathogens with horizontal gene transfer, and pathogens with documented human-to human transfer. Surprisingly, global drug use, time since drug discovery, mechanism of drug action, and pathogens with environmental reservoirs did not emerge as statistically robust predictors of drug resistance evolution in our analyses. To the best of our knowledge this work is the first systematic analysis of resistance evolution across such a wide range of human bacterial pathogens, encompassing the vast majority of common bacterial pathogens. Insights from our study may help guide public health policies and future studies on resistance control.
2. Why is vaccine resistance less common than drug resistance?
[-with David A Kennedy, Penn State]
In this work, I am developing a powerful, new C elegans - Orsay virus study system to investigate how timing of intervention and multiplicity of targets affect the evolution of resistance against drugs and vaccines. For this work I am developing candidate antivirals as well as RNAi-based “vaccine-like” interventions to examine resistance evolution against these interventions. Stay tuned for results!!!
Previous Research
1. How do bacterial social interactions affect virulence evolution? Bacteria exhibit a wide array of social interactions ranging from mutual-benefit and cooperation to competition and spite. In fact, almost all known lineages of bacteria produce costly anti-competitor toxins called bacteriocins that can kill closely related competitor strains while sparing clone-mates of the producers. Bacteriocin production is considered ‘spiteful’ due to the direct fitness costs to both the producers and target competitors. My doctoral research investigated how bacteriocin-mediated competition can be harnessed to limit harmful pathogen evolution. My work provided the first direct evolutionary link between virulence and spite in bacteria (Figure 1) by demonstrating that the evolution of increased virulence is associated with the evolution of reduced bacteriocin production in the insect-pathogenic bacteria Xenorhabdus spp [Bhattacharya et al 2019, Biology Letters]. This work motivates the testable hypothesis that maintaining selection for bacteriocin-production during therapy may constrain virulence evolution.
2. Investigating how bacterial interspecific competition can be harnessed to decelerate drug resistance evolution. Rapidly spreading antibiotic resistance has led to the need for novel alternatives and sustainable strategies for antimicrobial use. Bacteriocins are a class of proteinaceous anti-competitor toxins under consideration as novel therapeutic agents. As part of my doctroal research, I examined how bacterial competition may be utilized to decelerate the evolution of bacteriocin resistance . We showed that incorporating live heterospecific competitors in conjunction with antimicrobials (specfically bacteriocins) could limit the evolution of antimicrobial resistance by competitively suppressing drug resistant variants [Bhattacharya et al, 2019, Evolutionary Applications]. This work demonstrated a powerful new, non-pharmacological approach to slow down the evolution of drug resistance.
3. How is "spite" maintained in bacterial populations? Bacteriocins are costly anticompetitor toxins ubiquitously produced across the bacterial kingdom that kill closely related competitor strains but do not kill clonemates of the producer cells. However, bacteriocin production is energetically costly, and deemed a 'suicide' mission as producer cells often must lyse to release these large proteinaceous toxins. Owing to direct fitness costs on both producers and target competitors, bacteriocin production is considered "spiteful". In fact, it is a rare example of spite in nature. How is such a costly trait maintained by selection? I investigated key theoretical predictions about the role of phenotypic plasticity in maintaining this costly trait in natural isolates of the insect-pathogenic bacteria, Xenorhabdus spp. We found that costly bacteriocins are produced even in the absence of target competitors, thus challenging the conventional assumption that bacteriocin production is a ‘suicide mission’ [Bhattacharya et al 2018, Ecology and Evolution].