Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria

By Dao Nguyen, Amruta Joshi-Datar, F. Lépine, Elizabeth Bauerle, O. Olakanmi, Karlyn D. Beer, G. McKay, R. Siehnel, James Schafhauser, Yun Wang and 2 more. Science, 2011

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During growth arrest, bacteria tolerate the presence of antibiotics, thanks to mechanisms that protect against oxidant stress. Bacteria become highly tolerant to antibiotics when nutrients are limited. The inactivity of antibiotic targets caused by starvation-induced growth arrest is thought to be a key mechanism producing tolerance. Here we show that the antibiotic tolerance of nutrient-limited and biofilm Pseudomonas aeruginosa is mediated by active responses to starvation, rather than by the passive effects of growth arrest. The protective mechanism is controlled by the starvation-signaling stringent response (SR), and our experiments link SR-mediated tolerance to reduced levels of oxidant stress in bacterial cells. Furthermore, inactivating this protective mechanism sensitized biofilms by several orders of magnitude to four different classes of antibiotics and markedly enhanced the efficacy of antibiotic treatment in experimental infections.

Subfields: Endocrinology, Molecular Biology, Molecular Medicine

View Paper: https://www.semanticscholar.org/paper/afcaaf23e9553ea44aa4f3788b9f7c616056be73

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Citations in the corpus

Surviving as a community: antibiotic tolerance and persistence in bacterial biofilms (2019, background): “Nutrient starvation, a common environmental situation encountered during both biofilm formation and entrance into stationary phase could promote antibiotic tolerance and persister cell formation by triggering the stringent response (Nguyen et al., 2011).”
Biofilms as Promoters of Bacterial Antibiotic Resistance and Tolerance (2020, background): “The SR has been related to reduced susceptibility to ofloxacin [92,93], meropenem, colistin [92], and gentamicin [92,94,95] in P.”
Mechanisms of bacterial persistence during stress and antibiotic exposure (2016, background): “Like TisB, HokB is a membrane-targeted type I toxin that disrupts the proton-motive force to impair ATP synthesis and induce dormancy (Fig.”
Antibiotic resistance and persistence—Implications for human health and treatment perspectives (2020, neutral): “2) (Dorr et al , 2010; Moker et al , 2010; Nguyen et al , 2011; Leung & Levesque, 2012; Vega et al , 2012; Amato et al , 2013; Bernier et al , 2013; Vulin et al , 2018; Rowe et al , 2020).”
Molecular mechanisms underlying bacterial persisters. (2014, positive): “For instance, the fraction of persisters increases during nutrient limitation and during diauxic carbon-source transition (Amato et al., 2013; Bernier et al., 2013; Fung et al., 2010; Keren et al., 2004a; Leung and Lévesque, 2012; Nguyen et al., 2011).”
Staphylococcus aureus biofilms: recent developments in biofilm dispersal (2014, background): “Studies have linked the stringent response to virulence and biofilm formation in multiple bacterial species (Lemos et al., 2004; Nguyen et al., 2011; Vogt et al., 2011; Chavez de Paz et al., 2012; He et al., 2012; Wexselblatt et al., 2012; Sugisaki et al., 2013).”
The importance of the viable but non-culturable state in human bacterial pathogens (2014, background): “It is well established that bacteria in biofilms are starved and this starvation response confers antibiotic resistance (Nguyen et al., 2011).”
Pseudomonas aeruginosa Lifestyle: A Paradigm for Adaptation, Survival, and Persistence (2017, background): “Stringent response and RelA/SpoT activity for production of ppGpp were found to be crucial for regulation of virulence factor production (Erickson et al., 2004; Viducic et al., 2006; Boes et al., 2008; Nguyen et al., 2011; Vogt et al., 2011).”
Bacterial Persister Cell Formation and Dormancy (2013, background): “(31) confirmed the much-earlier work of Korch et al.”