gram negative rods are often treated with aminoglycosides

We reasoned that, by enhancing aminoglycosides, this mechanism could be used to lower the antibiotic concentration required to treat infections, and would thereby reduce the risk of nephrotoxicity and ototoxicity to patients ( Fig 1B).įig 1. We previously uncovered a mechanism by which specific metabolites enabled high concentrations of aminoglycosides to eradicate E. Meanwhile, metabolically active cells continue to grow, and remain susceptible to antibiotic treatment ( Fig 1A). Tolerance is a distinct phenotype from resistance which requires a genetic modification, allows cells to grow in the presence of antibiotics, and is measured by minimum inhibitor concentration. A primary mechanism of this phenotype results from a sub-population of cells entering a metabolically dormant state, allowing them to tolerate growth-dependent antibiotics. This phenomenon, called “phenotypic tolerance” or alternately “bacterial persistence”, plays an important role in the duration and outcome of treatments, as well as the total amount of antibiotic administered. Percent resistance (and reference) is indicated.īacteria are capable of surviving antibiotic treatment without possessing genetic resistance factors. Gram-negative pathogen resistance to antibiotics. Adjuvants that lower the concentration of aminoglycoside necessary to kill bacteria could be transformative, and would particularly improve treatment of chronic and drug-resistant infections. As a result, aminoglycosides are typically reserved as a second-line antibiotic treatment.

However, clinicians must balance the efficacy of aminoglycosides with the potential for toxic side effects in patients, which include nephrotoxicity and ototoxicity. For this reason, aminoglycoside use has increased in recent years. These drugs cause translational inhibition and misreading of tRNAs by targeting the 30S subunit of the bacterial ribosome and have not succumbed to the same rise in resistance as fluoroquinolone, β-lactam, and cephalosporin antibiotics ( Table 1). g., Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa).

Aminoglycosides, one of the three major classes of antibiotics, are highly bactericidal and are commonly used to treat serious Gram-negative bacterial infections ( e. Given the important role of bacterial metabolism in antibiotic susceptibility, we reasoned that a strategy to rescue these antibiotics through metabolic intervention could improve problematic antibiotics and expand the current antibiotic arsenal. Many antibiotics are limited by low potency or toxic side effects in humans. Thus, to combat the rise of antibiotic resistance, it is imperative to improve the antibiotics presently available. Creating new antibiotics is both costly and timely, evidenced by the dearth of FDA-approved antibiotics in recent years. Over the past fifty years, antibiotic resistance has become a major public health hazard, causing tens of thousands of deaths and costing billions of dollars to treat. This work forwards a mechanism-based strategy to improve existing antibiotics by mitigating their toxic side effects. Additionally, we discovered that mannitol could directly protect human kidney cells from aminoglycoside cytotoxicity, independent of the metabolite’s effect on bacteria. Surprisingly, within starved populations, we observed rare cells (3%) that divided without added nutrients. By single-cell microscopy, we demonstrate that stationary-phase cells, while non-dividing, actively maintain a growth-arrested state that is not reversed by metabolite addition. We go on to show that this effect improved treatment of biofilms, did not increase aminoglycoside resistance, and was due to the generation of proton-motive force (PMF). Here, we employed this mechanism to greatly boost the activity of low concentrations of aminoglycosides against prevalent Gram-negative pathogens ( Escherichia coli, Salmonella enterica, and Klebsiella pneumoniae), suggesting that less toxic drug concentrations might be used effectively in patients. High antibiotic concentrations are often required to treat dormant, non-dividing bacteria, though previous studies show that aminoglycosides can be activated against such bacteria by specific metabolites. Aminoglycosides, antibiotics with excellent activity and low bacterial resistance, are hampered by dose-dependent toxic effects in patients (nephrotoxicity, ototoxicity). The lack of new antibiotics necessitates the improvement of existing ones, many of which are limited by toxic side effects.

Gram negative rods are often treated with aminoglycosides