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Alternating antibiotics render resistant bacteria beatable.

Richardson L - PLoS Biol. (2015)

View Article: PubMed Central - PubMed

Affiliation: Public Library of Science, San Francisco, California, United States of America.

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To help mimic more challenging clinical scenarios, the bacteria used in the in vitro model of infection contained a gene that encodes a multidrug efflux pump, the genomic amplification of which results in increased drug resistance to both drugs... Despite the presence and amplification of the efflux pump, the authors identified sequential treatments that killed the bacteria when monotherapies and combination therapies failed to do so... First, the authors tested whether a sequential therapy could outperform monotherapy or combination therapy (Fig. 1)... The combination therapy resulted in the greatest single-season inhibition (a nearly 95% reduction in cell density), but, by the end of the experiment, the cell densities rebounded, consistent with drug resistance... A follow-up experiment revealed that five of these treatments truly eliminated the entire bacterial population, whereas the other 11 had varying results... By contrast, neither the combination therapy nor either of the monotherapies achieved bacterial clearance... ERY and DOX act synergistically when given in combination, but, even at high doses, the combination treatment is not able to kill a bacterial population, as drug resistance still develops... Undeterred by this assumption, the authors tested whether any sequential treatments of ERY and DOX exhibit collateral sensitivity... When using ERY for multiple seasons followed by one season of DOX treatment, the authors saw a significant increase in cell density, consistent with cross-resistance... However, when they treated with DOX for multiple seasons followed by one season of ERY, they saw a significant reduction in cell density, consistent with a collateral sensitivity... Given these different results, this drug pairing is said to have a nonreciprocal collateral sensitivity... While the exact mechanism behind the nonreciprocal collateral sensitivity of DOX and ERY is still unknown, the authors hypothesized that it is related to the different efflux efficiencies of the two drugs by the multidrug pump... When they deleted the gene for this pump, there was an approximately 95% decrease in the amount of ERY needed to halve the cell density, suggesting that ERY is very efficiently pumped out of the cells... For DOX, there was just a 77% decrease, indicating a slower efflux rate.

No MeSH data available.


Can the sequential treatment of a bacterium with two antibiotics, in blue and green, have a greater efficacy than when the same antibiotics are combined into a cocktail, shown in red?The circles depict each of eight sequential “seasons,” with diameter reflecting population density in that season. Black bars at the right indicate the total cumulative bacterial population density, ΣOD(T).
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pbio.1002105.g001: Can the sequential treatment of a bacterium with two antibiotics, in blue and green, have a greater efficacy than when the same antibiotics are combined into a cocktail, shown in red?The circles depict each of eight sequential “seasons,” with diameter reflecting population density in that season. Black bars at the right indicate the total cumulative bacterial population density, ΣOD(T).

Mentions: First, the authors tested whether a sequential therapy could outperform monotherapy or combination therapy (Fig. 1). The combination therapy resulted in the greatest single-season inhibition (a nearly 95% reduction in cell density), but, by the end of the experiment, the cell densities rebounded, consistent with drug resistance. However, they did identify 16 sequential treatment patterns that cleared the bacteria. A follow-up experiment revealed that five of these treatments truly eliminated the entire bacterial population, whereas the other 11 had varying results. By contrast, neither the combination therapy nor either of the monotherapies achieved bacterial clearance.


Alternating antibiotics render resistant bacteria beatable.

Richardson L - PLoS Biol. (2015)

Can the sequential treatment of a bacterium with two antibiotics, in blue and green, have a greater efficacy than when the same antibiotics are combined into a cocktail, shown in red?The circles depict each of eight sequential “seasons,” with diameter reflecting population density in that season. Black bars at the right indicate the total cumulative bacterial population density, ΣOD(T).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390301&req=5

pbio.1002105.g001: Can the sequential treatment of a bacterium with two antibiotics, in blue and green, have a greater efficacy than when the same antibiotics are combined into a cocktail, shown in red?The circles depict each of eight sequential “seasons,” with diameter reflecting population density in that season. Black bars at the right indicate the total cumulative bacterial population density, ΣOD(T).
Mentions: First, the authors tested whether a sequential therapy could outperform monotherapy or combination therapy (Fig. 1). The combination therapy resulted in the greatest single-season inhibition (a nearly 95% reduction in cell density), but, by the end of the experiment, the cell densities rebounded, consistent with drug resistance. However, they did identify 16 sequential treatment patterns that cleared the bacteria. A follow-up experiment revealed that five of these treatments truly eliminated the entire bacterial population, whereas the other 11 had varying results. By contrast, neither the combination therapy nor either of the monotherapies achieved bacterial clearance.

View Article: PubMed Central - PubMed

Affiliation: Public Library of Science, San Francisco, California, United States of America.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

To help mimic more challenging clinical scenarios, the bacteria used in the in vitro model of infection contained a gene that encodes a multidrug efflux pump, the genomic amplification of which results in increased drug resistance to both drugs... Despite the presence and amplification of the efflux pump, the authors identified sequential treatments that killed the bacteria when monotherapies and combination therapies failed to do so... First, the authors tested whether a sequential therapy could outperform monotherapy or combination therapy (Fig. 1)... The combination therapy resulted in the greatest single-season inhibition (a nearly 95% reduction in cell density), but, by the end of the experiment, the cell densities rebounded, consistent with drug resistance... A follow-up experiment revealed that five of these treatments truly eliminated the entire bacterial population, whereas the other 11 had varying results... By contrast, neither the combination therapy nor either of the monotherapies achieved bacterial clearance... ERY and DOX act synergistically when given in combination, but, even at high doses, the combination treatment is not able to kill a bacterial population, as drug resistance still develops... Undeterred by this assumption, the authors tested whether any sequential treatments of ERY and DOX exhibit collateral sensitivity... When using ERY for multiple seasons followed by one season of DOX treatment, the authors saw a significant increase in cell density, consistent with cross-resistance... However, when they treated with DOX for multiple seasons followed by one season of ERY, they saw a significant reduction in cell density, consistent with a collateral sensitivity... Given these different results, this drug pairing is said to have a nonreciprocal collateral sensitivity... While the exact mechanism behind the nonreciprocal collateral sensitivity of DOX and ERY is still unknown, the authors hypothesized that it is related to the different efflux efficiencies of the two drugs by the multidrug pump... When they deleted the gene for this pump, there was an approximately 95% decrease in the amount of ERY needed to halve the cell density, suggesting that ERY is very efficiently pumped out of the cells... For DOX, there was just a 77% decrease, indicating a slower efflux rate.

No MeSH data available.