Spectrum of antibacterial activity and mode of action of a novel tris-stilbene bacteriostatic compound

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Abstract

The spectrum of activity and mode of action of a novel antibacterial agent, 135C, was investigated using a range of microbiological and genomic approaches. Compound 135C was active against Gram-positive bacteria with MICs for Staphylococcus aureus ranging from 0.12-0.5 mu g/ml. It was largely inactive against Gram-negative bacteria. The compound showed bacteriostatic activity in time-kill studies and did not elicit bacterial cell leakage or cell lysis. Checkerboard assays showed no synergy or antagonism when 135C was combined with a range of other antibacterials. Multi-step serial passage of four S. aureus isolates with increasing concentrations of 135C showed that resistance developed rapidly and was stable after drug-free passages. Minor differences in the fitness of 135C-resistant strains and parent wildtypes were evident by growth curves, but 135C-resistant strains did not show cross-resistance to other antibacterial agents. Genomic comparison of resistant and wildtype parent strains showed changes in genes encoding cell wall teichoic acids. 135C shows promising activity against Gram-positive bacteria but is currently limited by the rapid resistance development. Further studies are required to investigate the effects on cell wall teichoic acids and to determine whether the issue of resistance development can be overcome.

Original languageEnglish
Article number6912
Number of pages9
JournalScientific Reports
Volume8
DOIs
Publication statusPublished - 2 May 2018

Cite this

@article{c28001ea307e41e483d32615e5d1afca,
title = "Spectrum of antibacterial activity and mode of action of a novel tris-stilbene bacteriostatic compound",
abstract = "The spectrum of activity and mode of action of a novel antibacterial agent, 135C, was investigated using a range of microbiological and genomic approaches. Compound 135C was active against Gram-positive bacteria with MICs for Staphylococcus aureus ranging from 0.12-0.5 mu g/ml. It was largely inactive against Gram-negative bacteria. The compound showed bacteriostatic activity in time-kill studies and did not elicit bacterial cell leakage or cell lysis. Checkerboard assays showed no synergy or antagonism when 135C was combined with a range of other antibacterials. Multi-step serial passage of four S. aureus isolates with increasing concentrations of 135C showed that resistance developed rapidly and was stable after drug-free passages. Minor differences in the fitness of 135C-resistant strains and parent wildtypes were evident by growth curves, but 135C-resistant strains did not show cross-resistance to other antibacterial agents. Genomic comparison of resistant and wildtype parent strains showed changes in genes encoding cell wall teichoic acids. 135C shows promising activity against Gram-positive bacteria but is currently limited by the rapid resistance development. Further studies are required to investigate the effects on cell wall teichoic acids and to determine whether the issue of resistance development can be overcome.",
keywords = "RESISTANT STAPHYLOCOCCUS-AUREUS, TEICHOIC-ACID SYNTHESIS, ANTIBIOTIC-RESISTANCE, OUTER-MEMBRANE, FITNESS COSTS, SUSCEPTIBILITY, AGENTS, BIOSYNTHESIS, POLYCATIONS, ACQUISITION",
author = "Man, {Nikki Y. T.} and Knight, {Daniel R.} and Stewart, {Scott G.} and McKinley, {Allan J.} and Riley, {Thomas V.} and Hammer, {Katherine A.}",
year = "2018",
month = "5",
day = "2",
doi = "10.1038/s41598-018-25080-w",
language = "English",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group - Macmillan Publishers",

}

TY - JOUR

T1 - Spectrum of antibacterial activity and mode of action of a novel tris-stilbene bacteriostatic compound

AU - Man, Nikki Y. T.

AU - Knight, Daniel R.

AU - Stewart, Scott G.

AU - McKinley, Allan J.

AU - Riley, Thomas V.

AU - Hammer, Katherine A.

PY - 2018/5/2

Y1 - 2018/5/2

N2 - The spectrum of activity and mode of action of a novel antibacterial agent, 135C, was investigated using a range of microbiological and genomic approaches. Compound 135C was active against Gram-positive bacteria with MICs for Staphylococcus aureus ranging from 0.12-0.5 mu g/ml. It was largely inactive against Gram-negative bacteria. The compound showed bacteriostatic activity in time-kill studies and did not elicit bacterial cell leakage or cell lysis. Checkerboard assays showed no synergy or antagonism when 135C was combined with a range of other antibacterials. Multi-step serial passage of four S. aureus isolates with increasing concentrations of 135C showed that resistance developed rapidly and was stable after drug-free passages. Minor differences in the fitness of 135C-resistant strains and parent wildtypes were evident by growth curves, but 135C-resistant strains did not show cross-resistance to other antibacterial agents. Genomic comparison of resistant and wildtype parent strains showed changes in genes encoding cell wall teichoic acids. 135C shows promising activity against Gram-positive bacteria but is currently limited by the rapid resistance development. Further studies are required to investigate the effects on cell wall teichoic acids and to determine whether the issue of resistance development can be overcome.

AB - The spectrum of activity and mode of action of a novel antibacterial agent, 135C, was investigated using a range of microbiological and genomic approaches. Compound 135C was active against Gram-positive bacteria with MICs for Staphylococcus aureus ranging from 0.12-0.5 mu g/ml. It was largely inactive against Gram-negative bacteria. The compound showed bacteriostatic activity in time-kill studies and did not elicit bacterial cell leakage or cell lysis. Checkerboard assays showed no synergy or antagonism when 135C was combined with a range of other antibacterials. Multi-step serial passage of four S. aureus isolates with increasing concentrations of 135C showed that resistance developed rapidly and was stable after drug-free passages. Minor differences in the fitness of 135C-resistant strains and parent wildtypes were evident by growth curves, but 135C-resistant strains did not show cross-resistance to other antibacterial agents. Genomic comparison of resistant and wildtype parent strains showed changes in genes encoding cell wall teichoic acids. 135C shows promising activity against Gram-positive bacteria but is currently limited by the rapid resistance development. Further studies are required to investigate the effects on cell wall teichoic acids and to determine whether the issue of resistance development can be overcome.

KW - RESISTANT STAPHYLOCOCCUS-AUREUS

KW - TEICHOIC-ACID SYNTHESIS

KW - ANTIBIOTIC-RESISTANCE

KW - OUTER-MEMBRANE

KW - FITNESS COSTS

KW - SUSCEPTIBILITY

KW - AGENTS

KW - BIOSYNTHESIS

KW - POLYCATIONS

KW - ACQUISITION

U2 - 10.1038/s41598-018-25080-w

DO - 10.1038/s41598-018-25080-w

M3 - Article

VL - 8

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 6912

ER -