time-lapse-epifluorescence-microscopy-imaging-pseudomonas-aeruginosa

Time-Lapse Epifluorescence Microscopy Imaging of <i>Pseudomonas aeruginosa</i> and <i>Staphylococcus aureus</i> Heterogeneous Phenotypes

Antibiotic persistence is a phenomenon in which a small number of bacterial cells in a genetically susceptible population survive antibiotic treatment ...

Uconn Health

Antibiotic resistance is a major danger to public health that threatens to claim the lives of millions of people per year within the next few decades. Years of necessary administration and excessive application of antibiotics have selected for strains that are resistant to many of our currently available treatments. Due to the high costs and difficulty of developing new antibiotics, the emergence of resistant bacteria is outpacing the introduction of new drugs to fight them. To overcome this problem, many researchers are focusing on developing antibacterial therapeutic strategies that are "resistance-resistant"-regimens that slow or stall resistance development in the targeted pathogens. In this mini review, we outline major examples of novel resistance-resistant therapeutic strategies. We discuss the use of compounds that reduce mutagenesis and thereby decrease the likelihood of resistance emergence. Then, we examine the effectiveness of antibiotic cycling and evolutionary steering, in which a bacterial population is forced by one antibiotic toward susceptibility to another antibiotic. We also consider combination therapies that aim to sabotage defensive mechanisms and eliminate potentially resistant pathogens by combining two antibiotics or combining an antibiotic with other therapeutics, such as antibodies or phages. Finally, we highlight promising future directions in this field, including the potential of applying machine learning and personalized medicine to fight antibiotic resistance emergence and out-maneuver adaptive pathogens.

Resistance-resistant antibacterial treatment strategies.

If left unchecked, infections involving antibiotic-refractory bacteria are expected to cause millions of deaths per year in the coming decades. Beyond genetically resistant bacteria, persisters, which are genetically susceptible cells that survive antibiotic doses that kill the rest of the clonal population, can potentially contribute to treatment failure and infection relapse. Stationary-phase bacterial cultures are enriched with persisters, and it has been shown that stimulating these populations with exogenous nutrients can reduce persistence to different classes of antibiotics, including topoisomerase-targeting fluoroquinolones (FQs). In this study, we show that adding glucose and amino acids to nutrient-starved  cultures enhanced their sensitivity to FQs, including delafloxacin (Dela)-a drug that was recently approved for treating staphylococcal infections. We found that while the added nutrients increased nucleic acid synthesis, this increase was not required to sensitize  to FQs. We further demonstrate that addition of these nutrients increases membrane potential and the ability to generate harmful reactive oxygen species (ROS) during FQ treatment. Chelating iron, scavenging hydroxyl radicals, and limiting oxygenation during FQ treatment and during recovery following FQ treatment rescued nutrient-stimulated . In all, our data suggest that while nutrient stimulation increases the activity of FQ targets in stationary-phase , the resulting generation of ROS, presumably made possible through metabolic upregulation, is the primary driver of increased sensitivity to these drugs.IMPORTANCE causes many chronic and relapsing infections because of its ability to endure host immunity and antibiotic therapy. While several studies have focused on the nutrient requirements for the formation and maintenance of staphylococcal infections, the effects of the nutrient environment on bacterial responses to antibiotic treatment remain understudied. Here, we show that adding nutrients to starved  activates biosynthetic processes, including DNA synthesis, but it is the generation of harmful reactive oxidants that sensitizes  to DNA topoisomerase-targeting FQs. Our results suggest that the development of approaches aimed at perturbing metabolism and increasing oxidative stress can potentiate the bactericidal activity of FQs against antibiotic-tolerant .

Article	Year
Resistance-resistant antibacterial treatment strategies. Frontiers in antibiotics\| PubMed ID: 36845830	2023
Metabolites augment oxidative stress to sensitize antibiotic-tolerant to fluoroquinolones. mBio\| PubMed ID: 39475229	2024

Jonathan I. Batchelder

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