Multidrug Tolerance of Biofilms and Persister Cells

K. Lewis

1 Biofilms and Persisters 108

1.1 Multidrug Resistance and Multidrug Tolerance, Two Mechanistically

Distinct Menaces 111

  1. 2 In Search of the Mechanism of Persister Formation 113
  2. 3 A Generalized Hunt for Persister Genes 116
  3. 4 Persisters and Stochastic Phenomena 117
  4. 5 Is Multidrug Tolerance Transmissible? 119
  5. 6 Persisters in Yeast Biofilms 120

2 In Search of Therapy: Persister Eradication 121

  1. 1 Pulse-Dosing with a Conventional Antibiotic 123
  2. 2 Sterilizing Antibiotics 125

3 Conclusions 126

References 127

Abstract Bacterial populations produce a small number of dormant persister cells that exhibit multidrug tolerance. All resistance mechanisms do essentially the same thing: prevent the antibiotic from hitting a target. By contrast, tolerance apparently works by shutting down the targets. Bactericidal antibiotics kill bacteria by corrupting their targets, rather than merely inhibiting them. Shutting down the targets then protects from killing. The number of persisters in a growing population of bacteria rises at mid-log and reaches a maximum of approximately 1% at stationary state. Similarly, slow-growing biofilms produce substantial numbers of persisters. The ability of a biofilm to limit the access of the immune system components, and the ability of persisters to sustain an antibiotic attack could then account for the recalcitrance of such infections in vivo and for their relapsing nature. Isolation of Escherichia coli persisters by lysing a population or by sorting GFP-expressing cells with diminished translation allowed to obtain a gene expression profile.

K. Lewis

Antimicrobial Discovery Center and Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, 02459 USA k.lewis @

T. Romeo (ed.), Bacterial Biofilms.

Current Topics in Microbiology and Immunology 322.

© Springer-Verlag Berlin Heidelberg 2008

The profile indicated downregulated biosynthetic pathways, consistent with their dormant nature, and indicated overexpression of toxin/antitoxin (TA) modules. Stochastic overexpression of toxins that inhibit essential functions such as translation may contribute to persister formation. Ectopic expression of RelE, MazF, and HipA toxins produced multidrug tolerant cells. Apart from TA modules, glpD and plsB were identified as potential persister genes by overexpression cloning of a genomic library and selection for antibiotic tolerance. Yeast Candida albicans forms recalcitrant biofilm infections that are tolerant to antibiotics, similarly to bacterial biofilms. C. albicans biofilms produce multidrug tolerant persisters that are not mutants, but rather phenotypic variants of the wild type. Unlike bacterial persisters, however, C. albicans persisters were only observed in a biofilm, but not in a planktonic stationary population. Identification of persister genes opens the way to a rational design of anti-biofilm therapy. Combination of a conventional antibiotic with a compound inhibiting persister formation or maintenance may produce an effective therapeutic. Other approaches to the problem include sterile-surface materials, prodrug antibiotics, and cyclical application of conventional antimicrobials.

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