Antimicrobial-resistant (AMR) bacteria cause approximately 2 million infections every year in the US. According to the CDC, Salmonella alone is responsible for over 200,000 of those cases, and is thus a serious threat. The study “Twin arginine translocation (Tat) mutants in Salmonella enterica serovar Typhimurium have increased susceptibility to cell wall targeting antibiotics” published in FEMS Microbes investigates the link between the Tat protein secretion system and antibiotic resistances in Salmonella species. Adrienne Brauer explains for the #FEMSmicroBlog how characterizing deletion mutants in this important export system can help tackle the AMR crisis. #FascinatingMicrobes
The antibiotic resistance crisis
It is well established that the problem of antibiotic resistance lies in the ability of bacteria to evolve quickly and “outsmart us”. Constant use and misuse of antibiotics only give them more opportunities to develop resistance.
To make matters worse, bacteria can exchange genetic information via horizontal gene transfer, making it easier to pass antibiotic resistances to one another. Like this, bacteria continue to acquire resistances to the drugs we treat them with, possibly resulting in untreatable and fatal infections.
To treat bacterial infections, β-lactam antibiotics are commonly used. These target enzymes that are involved in producing the essential bacterial cell wall structure peptidoglycan. Unfortunately, β-lactam resistance is prevalent in bacteria, and understanding the mechanisms behind this is crucial to our response to the growing AMR crisis.
Understanding β-lactam resistance in bacteria is crucial to our response to the growing AMR crisis.
Characterizing β-lactam sensitivity in Salmonella
The paper “Twin arginine translocation (Tat) mutants in Salmonella enterica serovar Typhimurium have increased susceptibility to cell wall targeting antibiotics” published in FEMS Microbes explores the mechanism by which a deletion in a Salmonella protein secretion system increases the sensitivity to cell-targeting antibiotics.
Tat is a protein export system that moves proteins from the cytoplasm to the periplasm of the bacterium. Salmonella has 30 known Tat substrates involved in peptidoglycan maintenance, proton motive force, and anaerobic respiration, to name a few.
The paper shows experimentally that only a few key substrates out of the 30 are responsible for the tat phenotype; AmiA, AmiC, SufI, and MepK. All of them are involved in maintaining the cell wall.
Even more exciting, the study found that deleting genes encoding Tat-translocated hydrogenase subunits results in a decreased proton motive force. This further inhibited the translocation of the four previously described substrates and therefore exhibited increased β-lactam sensitivity.
Proper peptidoglycan maintenance is critical to withstand stressors like antibiotics. This work demonstrates what happens when that maintenance is disrupted. Similarly, the study demonstrates the potential of using Tat or its substrates as drug targets to increase the effectiveness of antibiotics.
From bench to bedside
How could we bridge the gap between identifying a bacterial drug target and making a medical impact? The first step would be to screen for drugs that successfully target Tat or its substrates and increase bacterial killing in combination with antibiotics.
After verifying a list of promising drugs, help from experts in other fields is needed to determine their safety and dosage in animal models. If the drug is safe and effective in animal models, it eventually makes its way to clinical trials in humans.
This process usually takes a decade and includes dozens of more steps. However tedious, the impact of this work on human health is great, and it could not be accomplished without first studying the basic science of bacterial physiology.
- Read also the blog entry for the #FEMSmicroBlog: Where are we? Antimicrobial Resistance 2020 by Eleni Koursari
Adrienne Brauer is a first-year graduate student in the Plant & Microbial Biosciences program at Washington University in St. Louis (US). Adrienne studied the Tat system in Dr. Jeremy Ellermeier’s lab at Southeast Missouri State University for 3 years as an undergraduate. Adrienne also runs a microbiology-themed Instagram account aimed at increasing science communication.
About this blog section
The section #FascinatingMicrobes for the #FEMSmicroBlog explains the science behind a paper and highlights the significance and broader context of a recent finding. One of the main goals is to share the fascinating spectrum of microbes across all fields of microbiology.
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