Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics

Mo, Charlie Y.; Manning, Sara A.; Roggiani, Manuela; Culyba, Matthew J.; Samuels, Amanda N.; Sniegowski, Paul D.; Goulian, Mark; Kohli, Rahul M.

doi:10.1128/msphere.00163-16

Cited by 79 publications

(103 citation statements)

References 76 publications

(86 reference statements)

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“…Consistent with our conclusion that any mutagenic effects would have weak effects on adaptation to phages relative to the effects of growth inhibition, a long‐term experiment with Pseudomonas aeruginosa found no evidence that SOS‐induced mutagenesis accelerated the rate of adaptation to antibiotics over 200 generations (Torres‐Barceló et al ., ). Thus, despite strong evidence for mutagenic effects of antibiotics on some phenotypes (Kohanski et al ., ; Thi et al ., ; Mo et al ., ), the downstream effects of this for adaptation can be weak relative to other effects on physiology or growth, as they were in our experiment.…”

Section: Discussionmentioning

confidence: 50%

“…We therefore asked whether subinhibitory concentrations of four antibiotics were associated with altered mutation rates towards phage resistance in these conditions. We selected antibiotics either showing greater growth or survival after exposure to intermediate concentrations (nalidixic acid and tetracycline) or associated in other studies with mutagenic effects on other types of resistance (Jee et al ., ; Mo et al ., ) (ciprofloxacin and ampicillin). All our estimates for mutation rate to phage resistance were within approximately one order of magnitude of each other (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…First, although we accounted for variation of population size across our fluctuation assays, treatment effects could potentially also be influenced by any effect of changes in population density due to antibiotics on the tendency to under‐ or overestimate mutation rates, and by any other effects of antibiotics on bacterial growth dynamics not reflected in population density prior to plating, such as an altered relationship between final population size (Nt) and the number of genome replications during the growth phase of the assay (Frenoy & Bonhoeffer, ). Second, we tested a limited number of antibiotic concentrations and although there is evidence of mutagenesis at similar doses (Mo et al ., ), it may be that mutagenic effects occur only over a narrow range, where mechanisms such as SOS‐induced mutagenesis (Torres‐Barceló et al ., ) are triggered but cells remain viable (Couce & Blázquez, ). Third, the impact of any mutagenic effects will depend on the type of genetic changes driving adaptation to a new stress.…”

Section: Discussionmentioning

confidence: 99%

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Effects of prior exposure to antibiotics on bacterial adaptation to phages

Arias-Sánchez

Allen

Hall

2018

J of Evolutionary Biology

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Understanding adaptation to complex environments requires information about how exposure to one selection pressure affects adaptation to others. For bacteria, antibiotics and viral parasites (phages) are two of the most common selection pressures and are both relevant for treatment of bacterial infections: increasing antibiotic resistance is generating significant interest in using phages in addition or as an alternative to antibiotics. However, we lack knowledge of how exposure to antibiotics affects bacterial responses to phages. Specifically, it is unclear how the negative effects of antibiotics on bacterial population growth combine with any possible mutagenic effects or physiological responses to influence adaptation to other stressors such as phages, and how this net effect varies with antibiotic concentration. Here, we experimentally addressed the effect of pre-exposure to a wide range of antibiotic concentrations on bacterial responses to phages. Across 10 antibiotics, we found a strong association between their effects on bacterial population size and subsequent population growth in the presence of phages (which in these conditions indicates phage-resistance evolution). We detected some evidence of mutagenesis among populations treated with fluoroquinolones and b-lactams at sublethal doses, but these effects were small and not consistent across phage treatments. These results show that, although stressors such as antibiotics can boost adaptation to other stressors at low concentrations, these effects are weak compared to the effect of reduced population growth at inhibitory concentrations, which in our experiments strongly reduced the likelihood of subsequent phage-resistance evolution.

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Section: Discussionmentioning

confidence: 50%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effects of prior exposure to antibiotics on bacterial adaptation to phages

Arias-Sánchez

Allen

Hall

2018

J of Evolutionary Biology

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“…The SOS response is required for increased ofloxacin tolerance of starved biofilms during the posttreatment recovery phase. To firmly correlate the level of tolerance of the starved biofilms treated with fluoroquinolones with the level of induction of the SOS response, we used lexA variant strains that display different abilities to induce the SOS response (17). Inactivation of the self-cleavage of LexA (S119A) totally inhibits the SOS response.…”

Section: Resultsmentioning

confidence: 99%

Zinc Acetate Potentiates the Action of Tosufloxacin against Escherichia coli Biofilm Persisters

Usui

Yokoo

Tsutsumi

et al. 2019

Antimicrob Agents Chemother

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Formation of bacterial biofilms is a major health threat due to their high levels of tolerance to multiple antibiotics and the presence of persisters responsible for infection relapses. We previously showed that a combination of starvation and induction of SOS response in biofilm led to increased levels of persisters and biofilm tolerance to fluoroquinolones. In this study, we hypothesized that inhibition of the SOS response may be an effective strategy to target biofilms and fluoroquinolone persister cells. We tested the survival of Escherichia coli biofilms to different classes of antibiotics in starved and nonstarved conditions and in the presence of zinc acetate, a SOS response inhibitor. We showed that zinc acetate potentiates, albeit moderately, the activity of fluoroquinolones against E. coli persisters in starved biofilms. The efficacy of zinc acetate to increase fluoroquinolone activity, particularly that of tosufloxacin, suggests that such a combination may be a potential strategy for treating biofilm-related bacterial infections.

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“…These approaches involve inhibiting the SOS-mediated mutagenesis induced by drugs and thus improving their long-term viability. In these cases, LexA and RecA represent potential targets [53,54]. In fact, the number of SOS inhibitors is still limited and most of the studies use E. coli as model [55,56].…”

Section: New Compounds Able To Modulate the Sos Response In Staphylocmentioning

confidence: 99%

SOS Response and Staphylococcus aureus: Implications for Drug Development

Silva¹,

Diniz²,

Lima³

et al. 2017

The Rise of Virulence and Antibiotic Resistance in ≪i>Staphylococcus Aureus

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Damage in genetic material is induced through the action of several drugs (directly or indirectly). Specially, antimicrobials from quinolone class (such as ciproloxacin) induce DNA damage that promotes the formation of the RecA ilament leading to auto-cleavage of LexA and allows the expression of SOS genes, including the error-prone polymerase (like umuC). The SOS pathway plays a critical role in the acquisition of mutations that lead to the emergence of antibiotic-resistant bacteria and the spread of virulence factors. This chapter provides a comprehensive review about the SOS response of Staphylococcus aureus and the modulatory efects of new compounds (natural or synthetics) on this pathway. The efects of some SOS inhibitors are highlighted such as baicalein and aminocoumarins. Compounds able to prevent SOS response are extremely important to develop new combinatory approaches to inhibit S. aureus mutagenesis. The study of new SOS inductors could reveal new insights into the pathways used by S. aureus to acquire drug resistance; examples of these compounds are the lysine-peptoid hybrid LP5, cyclic peptide inhibitors, etc. These studies can impact the development of new drugs. In conclusion, we hope to provide essential information about the efects of compounds on SOS response from S. aureus.

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Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics

Cited by 79 publications

References 76 publications

Effects of prior exposure to antibiotics on bacterial adaptation to phages

Effects of prior exposure to antibiotics on bacterial adaptation to phages

Zinc Acetate Potentiates the Action of Tosufloxacin against Escherichia coli Biofilm Persisters

SOS Response and Staphylococcus aureus: Implications for Drug Development

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