College
College of Arts and Sciences
Mentor Information
Smitha Sivapragasam
Description
Antimicrobial resistance (AMR) is a critical global health threat, contributing to an estimated 4.95 million deaths associated with bacterial AMR in 2019. A key regulator of bacteria’s stringent stress response is the alarmone phosphorylated guanosines (p)ppGpp which shuts down most cell processes preserving survival. Firstly, bacteria exposed to DNA-damaging antibiotics undergo SOS (Save Our Soul) response promoting the formation of a “gambler” sub-population. Recent work suggests that (p)ppGpp binding to RNA polymerase influences SOS signaling in these gambler cells which initiate error-prone DNA repair to promote mutations to evolve and survive DNA damaging stress. Secondly, upon exposure to lethal doses of antibiotics, a subpopulation of bacteria shows increased levels of Obg GTPase protein that induces the expression of the HokB toxin, leading to collapse of membrane potential. This results in a dormant state that blocks the entry of antibiotics into cells in a (p)ppGpp dependent pathway which is described as a novel bacterial bet-hedging strategy to resist antibiotics. Therefore, we hypothesize that the alarmone (p)ppGpp mediates distinctive gambling and bet-hedging strategies, promoting resistance within bacteria exposed to antibiotics in the host or environment. Our hypothesis is based on research published in the past two decades that correlated antibiotic resistance to the synthesis of (p)ppGpp within cells upon exposure to DNA damaging antibiotics. We argue that understanding the mechanisms by which (p)ppGpp promotes antibiotic resistance and developing tools to diagnose antimicrobial resistance is of great necessity.
The (p)ppGpp Conundrum: Bacterial Gamblers and Bet-Hedgers Cash out on Antibiotic Resistance
Antimicrobial resistance (AMR) is a critical global health threat, contributing to an estimated 4.95 million deaths associated with bacterial AMR in 2019. A key regulator of bacteria’s stringent stress response is the alarmone phosphorylated guanosines (p)ppGpp which shuts down most cell processes preserving survival. Firstly, bacteria exposed to DNA-damaging antibiotics undergo SOS (Save Our Soul) response promoting the formation of a “gambler” sub-population. Recent work suggests that (p)ppGpp binding to RNA polymerase influences SOS signaling in these gambler cells which initiate error-prone DNA repair to promote mutations to evolve and survive DNA damaging stress. Secondly, upon exposure to lethal doses of antibiotics, a subpopulation of bacteria shows increased levels of Obg GTPase protein that induces the expression of the HokB toxin, leading to collapse of membrane potential. This results in a dormant state that blocks the entry of antibiotics into cells in a (p)ppGpp dependent pathway which is described as a novel bacterial bet-hedging strategy to resist antibiotics. Therefore, we hypothesize that the alarmone (p)ppGpp mediates distinctive gambling and bet-hedging strategies, promoting resistance within bacteria exposed to antibiotics in the host or environment. Our hypothesis is based on research published in the past two decades that correlated antibiotic resistance to the synthesis of (p)ppGpp within cells upon exposure to DNA damaging antibiotics. We argue that understanding the mechanisms by which (p)ppGpp promotes antibiotic resistance and developing tools to diagnose antimicrobial resistance is of great necessity.
