Biology subjects

Tavaddod, S.

Publications and source records attributed to Tavaddod, S..

4 recordsLinked to original sources

bioRxiv2024

Surface versus volume synthesis governs growth-dependent efficacy of a β-lactam antibiotic

The efficacy of {beta}-lactam antibiotics depends strongly on bacterial growth rate. This can lead to poor correlation between in vivo action and in vitro assays, hindering effective prescribing - yet the mechanisms underlying growth-rate dependent {beta}-lactam action remain unclear. Here, we investigate growth-rate dependent action of mecillinam, a {beta}-lactam that targets the elongation-mediating PBP2 peptidoglycan transpeptidase enzyme, on Escherichia coli cells. We show that mecillinam alters the balance between the rates of cell surface area and volume synthesis in a growth-rate dependent manner. Under mecillinam treatment, cell volume increases exponentially at a rate [fi]xed by the growth medium, but the cells ability to produce new surface area is compromised by the antibiotic. On rich medium, this imbalance leads to lysis, but on poor medium, slow-growing cells reach a new balance between surface area and volume synthesis, allowing sustained growth even at concentrations of mecillinam far above the EUCAST MIC value. A mathematical model based on surface area vs volume synthesis can quantitatively explain growth-medium dependent differences in mecillinam killing, as well as rescue from killing when cell morphology is perturbed in a microfluidic device. {beta}-lactam antibiotic action is mechanistically complex, yet our work suggests that simple conceptual principles can help understand the interplay between molecular mechanism and cell physiology, potentially contributing to more effective use of these drugs.

microbiology↗

bioRxiv2023

Bacterial aggregation triggered by low-level antibiotic-mediated lysis

Suspended bacterial aggregates play a central role in ocean biogeochemistry, industrial processes and probably many clinical infections - yet the factors that trigger aggregation remain poorly understood, as does the relationship between suspended aggregates and surface-attached biofilms. Here we show that very low doses of cell-wall targeting antibiotic, far below the minimal inhibitory concentration, can trigger aggregation of Escherichia coli cells. This occurs when a few cells lyse, releasing extracellular DNA - thus, cell-to-cell variability in antibiotic response leads to population-level aggregation. Although lysis-triggered aggregation echoes known trigger mechanisms for surface-attached biofilms, these aggregates appear to be of a distinct type, since they do not show typical biofilm characteristics such as protection from antibiotics, or increased biofilm-forming potential. Our work contributes to understanding the nature of bacterial aggregates and the factors that trigger their formation, and the consequences of widespread low-dose antibiotic exposure in the environment and in the body.

microbiology↗

bioRxiv2022

Urine production rate is critical in a model for catheter-associated urinary tract infection

Urinary catheters are used extensively in hospitals and long-term care and they are highly prone to infection. Understanding the pathways by which bacteria colonise a urinary catheter could guide strategies to mitigate infection, but quantitative models for this colonisation process are lacking. Here we present a mathematical model for bacterial colonisation of a urinary catheter, that integrates population dynamics and fluid dynamics. The model describes bacteria migrating up the outside surface of the catheter, spreading into the bladder and being swept through the catheter lumen. Computer simulations of the model reveal that clinical outcomes for long-term versus short-term catheterisation are controlled by different factors: the rate of urine production by the kidneys as opposed to urethral length, catheter surface properties and bacterial motility. Our work may help explain variable susceptibility to catheter-associated urinary tract infection (CAUTI) among individuals, and the mixed success of antimicrobial surface coatings. Our model suggests that for long-term catheterised patients, increasing fluid intake or reducing residual urine volume in the bladder may help prevent infection, while antimicrobial surface coatings are predicted to be effective only for short-term catheterised patients. Therefore, different catheter management strategies could be rationally targeted to long-term vs short-term catheterised patients.

biophysics↗

bioRxiv2020

Stability of β-lactam antibiotics in bacterial growth media

Laboratory assays such as MIC tests assume that antibiotic molecules are stable in the chosen growth medium - but rapid degradation has been observed for antibiotics including {beta}-lactams under some conditions in aqueous solution. Degradation rates in bacterial growth medium are less well known. Here, we develop a delay time bioassay that provides a simple way to estimate antibiotic stability in bacterial growth media. We use the bioassay to measure degradation half-lives of the {beta}-lactam antibiotics mecillinam, aztreonam and cefotaxime in widely-used bacterial growth media based on MOPS and Luria-Bertani (LB) broth. We find that mecillinam degradation can occur rapidly, with a half-life as short as 2 hours in MOPS medium at 37{degrees}C and pH 7.4, and 4-5 hours in LB, but that adjusting the pH and temperature can increase its stability to a half-life around 6 hours without excessively perturbing growth. Aztreonam and cefotaxime were found to have half-lives longer than 6 hours in MOPS medium at 37{degrees}C and pH 7.4, but still shorter than the timescale of a typical minimum inhibitory concentration (MIC) assay. Taken together, our results suggest that care is needed in interpreting MIC tests and other laboratory growth assays for {beta}-lactam antibiotics, since there may be significant degradation of the antibiotic during the assay.

pharmacology and toxicology↗