Collective antibiotic tolerance: mechanisms, dynamics and intervention

Meredith, Hannah R.; Srimani, Jaydeep K.; Lee, Anna J.; Lopatkin, Allison J.; Li, You

doi:10.1038/nchembio.1754

Cited by 131 publications

(120 citation statements)

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“…The mechanisms underlying the non-inherited antibiotic refractoriness of bacteria are diverse, and only partially understood (Hogan and Kolter, 2002;Lewis, 2010;Balaban et al, 2013;Orman and Brynildsen, 2013). Some forms of tolerance to lethal doses of antibiotics, for example, persistence, are associated with a strongly reduced metabolic activity, whereas others rely on active responses that confer (collective) adaptive resistance (Balaban et al, 2004;Butler et al, 2010;Lewis, 2010;Nguyen et al, 2011;Wakamoto et al, 2013;Meredith et al, 2015). Little is known regarding the role of antibiotic concentration gradients in facilitating the survival of nonresistant bacteria.…”

Section: Introductionmentioning

confidence: 99%

“…Antibiotic concentration gradients develop during treatment because of the tissue-dependent drug-penetration and periodic administration of the drug (Mukhopadhyay et al, 1994;Kaiser et al, 2014). Such gradients may act as safe havens for susceptible bacteria by providing regions that (transiently) support growth (Baquero and Negri, 1997;Fernández et al, 2011;Meredith et al, 2015). In addition to clinical settings, antibiotic gradients also arise in, for example, soil communities where narrow-spectrum antibiotics are locally released by antibiotic-producing bacteria establishing short-lived gradients (Romero et al, 2011;Vetsigian et al, 2011;.…”

Section: Introductionmentioning

confidence: 99%

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Density-dependent adaptive resistance allows swimming bacteria to colonize an antibiotic gradient

et al. 2015

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During antibiotic treatment, antibiotic concentration gradients develop. Little is know regarding the effects of antibiotic gradients on populations of nonresistant bacteria. Using a microfluidic device, we show that high-density motile Escherichia coli populations composed of nonresistant bacteria can, unexpectedly, colonize environments where a lethal concentration of the antibiotic kanamycin is present. Colonizing bacteria establish an adaptively resistant population, which remains viable for over 24 h while exposed to the antibiotic. Quantitative analysis of multiple colonization events shows that collectively swimming bacteria need to exceed a critical population density in order to successfully colonize the antibiotic landscape. After colonization, bacteria are not dormant but show both growth and swimming motility under antibiotic stress. Our results highlight the importance of motility and population density in facilitating adaptive resistance, and indicate that adaptive resistance may be a first step to the emergence of genetically encoded resistance in landscapes of antibiotic gradients.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Density-dependent adaptive resistance allows swimming bacteria to colonize an antibiotic gradient

et al. 2015

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“…Protective interactions are especially interesting in the context of antibiotic resistance, where they can affect the success of antibiotic treatment and influence the evolution of antibiotic resistance (16)(17)(18)(19)(20). For example, the well-known inoculum effect refers to the observation that inhibiting bacterial infections composed of more cells can require disproportionally more antibiotic (21).…”

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confidence: 99%

“…For example, the well-known inoculum effect refers to the observation that inhibiting bacterial infections composed of more cells can require disproportionally more antibiotic (21). Mechanisms that allow bacteria to help each other survive antibiotic exposure include the formation of protective structures like biofilms, coordination of a group response (via quorum sensing), or production of enzymes that modify and deactivate the target antibiotic (16,17).…”

mentioning

confidence: 99%

Oscillatory dynamics in a bacterial cross-protection mutualism

Yurtsev

Conwill

Gore

2016

Proc. Natl. Acad. Sci. U.S.A.

127

124

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Cooperation between microbes can enable microbial communities to survive in harsh environments. Enzymatic deactivation of antibiotics, a common mechanism of antibiotic resistance in bacteria, is a cooperative behavior that can allow resistant cells to protect sensitive cells from antibiotics. Understanding how bacterial populations survive antibiotic exposure is important both clinically and ecologically, yet the implications of cooperative antibiotic deactivation on the population and evolutionary dynamics remain poorly understood, particularly in the presence of more than one antibiotic. Here, we show that two Escherichia coli strains can form an effective crossprotection mutualism, protecting each other in the presence of two antibiotics (ampicillin and chloramphenicol) so that the coculture can survive in antibiotic concentrations that inhibit growth of either strain alone. Moreover, we find that daily dilutions of the coculture lead to large oscillations in the relative abundance of the two strains, with the ratio of abundances varying by nearly four orders of magnitude over the course of the 3-day period of the oscillation. At modest antibiotic concentrations, the mutualistic behavior enables long-term survival of the oscillating populations; however, at higher antibiotic concentrations, the oscillations destabilize the population, eventually leading to collapse. The two strains form a successful cross-protection mutualism without a period of coevolution, suggesting that similar mutualisms may arise during antibiotic treatment and in natural environments such as the soil.

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“…[1][2][3] According to the National Institute of Health, 4 up to 80% of human bacterial infections involve biofilm-associated microorganisms. For instance, biofilm formation plays a crucial role in microbe pathogenicity such as Legionnaire's disease, endocarditis, pneumonia accompanied by cystic fibrosis and infections of urogenital and gastrointestinal tracts.…”

Section: Introductionmentioning

confidence: 99%

Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases

Wiggers¹,

Crusca²,

Silva³

et al. 2017

J. Braz. Chem. Soc.

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Biofilms are widely present in many human chronic infections, often more resistant to treatment with antibiotics. Bacterial diguanylate cyclases (DGCs) synthesize cyclic dimeric guanosine monophosphate (c-di-GMP) from two guanosine-5'-triphosphate (GTP) molecules. c-di-GMP is a central second messenger controlling biofilm formation, turning this class of enzymes an attractive target to prevent and disrupt biofilms of pathogenic bacteria. Here, we apply an in silico ligand-and target-based hybrid method to screen potential DGC inhibitors from an FDA-approved drug databank. Mass spectrometry assays confirmed that seven screened compounds selectively bound to the GTP active site of P. aeruginosa WspR GGDEF domain. Four out of those, including the anti-inflammatory sulfasalazine and the anti-hypertensive eprosartan, inhibited distinct DGCs (P. aeruginosa WspR and E. coli YdeH) in the micromolar range. Sulfasalazine and eprosartan reduced aggregation in solution of E. coli overexpressing WspR or YdeH. Similar anti-aggregation effects were also observed for sulfasalazine-related anti-inflammatory drugs sulfadiazine and sulfathiazole, the latter a previously described anti-biofilm agent. The optimized pharmacokinetic properties and toxicological profiles of the DGC inhibitors could be promising candidates for new anti-microbial agents based on the drug reposition strategy.Keywords: c-di-GMP, diguanylate cyclase enzymes, bacterial biofilm, virtual screening, drug repositioning IntroductionBacterial biofilms, a multicellular community encased in an extracellular matrix, are commonly related to persistent infections, usually less susceptible to antibiotic treatments when compared to planktonic cells. [1][2][3] According to the National Institute of Health, 4 up to 80% of human bacterial infections involve biofilm-associated microorganisms. For instance, biofilm formation plays a crucial role in microbe pathogenicity such as Legionnaire's disease, endocarditis, pneumonia accompanied by cystic fibrosis and infections of urogenital and gastrointestinal tracts. 5,6 Furthermore, biofilm infections promote devastating effects on medical device implanted and immunocompromised individuals, representing a major medical and economic predicament. 7 The burden on public health due to chronic biofilm contaminations urge for the development of new chemotherapeutic approaches. Cellular processes controlling biofilm formation and dispersion, such as quorum sensing systems and metabolic pathways, are important targets for the discovery of new bioactive compounds. 8-10The second messenger bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) is a key regulator of bacterial behavior, especially controlling the switch between the motile planktonic and sedentary biofilm-associated lifestyles. Cyclic di-GMP stimulates the biosynthesis of adhesins and exopolysaccharide matrix substances in biofilms and inhibits various forms of motility. In general, low intracellular c-di-GMP levels are associated with freeswimming cells, whereas bacter...

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Collective antibiotic tolerance: mechanisms, dynamics and intervention

Cited by 131 publications

References 94 publications

Density-dependent adaptive resistance allows swimming bacteria to colonize an antibiotic gradient

Density-dependent adaptive resistance allows swimming bacteria to colonize an antibiotic gradient

Oscillatory dynamics in a bacterial cross-protection mutualism

Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases

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