Eagle Effect in Nonreplicating Persister Mycobacteria

Wu, Mu Lu; Tan, Jasmie; Dick, Thomas

doi:10.1128/aac.01476-15

Cited by 15 publications

(8 citation statements)

References 34 publications

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“…For three of the five genes tested, we found that CAM caused increased mRNA stability under hypoxia. This is consistent with CAM’s mechanism of action and published work (59–61). CAM inhibits elongation by preventing peptidyl transfer (62–64) and causing ribosomal stalling (65).…”

Section: Resultssupporting

confidence: 92%

mRNA Degradation Rates Are Coupled to Metabolic Status in Mycobacterium smegmatis

Vargas-Blanco

Zhou

Zamalloa

et al. 2019

mBio

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The success of Mycobacterium tuberculosis as a human pathogen is due in part to its ability to survive stress conditions, such as hypoxia or nutrient deprivation, by entering nongrowing states. In these low-metabolism states, M. tuberculosis can tolerate antibiotics and develop genetically encoded antibiotic resistance, making its metabolic adaptation to stress crucial for survival. Numerous bacteria, including M. tuberculosis, have been shown to reduce their rates of mRNA degradation under growth limitation and stress. While the existence of this response appears to be conserved across species, the underlying bacterial mRNA stabilization mechanisms remain unknown. To better understand the biology of nongrowing mycobacteria, we sought to identify the mechanistic basis of mRNA stabilization in the nonpathogenic model Mycobacterium smegmatis. We found that mRNA half-life was responsive to energy stress, with carbon starvation and hypoxia causing global mRNA stabilization. This global stabilization was rapidly reversed when hypoxia-adapted cultures were reexposed to oxygen, even in the absence of new transcription. The stringent response and RNase levels did not explain mRNA stabilization, nor did transcript abundance. This led us to hypothesize that metabolic changes during growth cessation impact the activities of degradation proteins, increasing mRNA stability. Indeed, bedaquiline and isoniazid, two drugs with opposing effects on cellular energy status, had opposite effects on mRNA half-lives in growth-arrested cells. Taken together, our results indicate that mRNA stability in mycobacteria is not directly regulated by growth status but rather is dependent on the status of energy metabolism. IMPORTANCE The logistics of tuberculosis therapy are difficult, requiring multiple drugs for many months. Mycobacterium tuberculosis survives in part by entering nongrowing states in which it is metabolically less active and thus less susceptible to antibiotics. Basic knowledge on how M. tuberculosis survives during these low-metabolism states is incomplete, and we hypothesize that optimized energy resource management is important. Here, we report that slowed mRNA turnover is a common feature of mycobacteria under energy stress but is not dependent on the mechanisms that have generally been postulated in the literature. Finally, we found that mRNA stability and growth status can be decoupled by a drug that causes growth arrest but increases metabolic activity, indicating that mRNA stability responds to metabolic status rather than to growth rate per se. Our findings suggest a need to reorient studies of global mRNA stabilization to identify novel mechanisms that are presumably responsible.

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Section: Resultssupporting

confidence: 92%

mRNA Degradation Rates Are Coupled to Metabolic Status in Mycobacterium smegmatis

Vargas-Blanco

Zhou

Zamalloa

et al. 2019

mBio

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“…The exposure to the two fluoroquinolones ciprofloxacin and ofloxacin, and the aminoglycoside gentamicin produce an increasing number of persisters above 0.15, 0.5, and 0.75 µg/mL, respectively. Examples of an in vitro more-drug-kills-fewer Eagle effect include vancomycin against C. difficile [ 155 ] and fluoroquinolones against M. smegmatis [ 156 ]. An in vivo model illustrated this effect in C. diphtheriae treated with amoxicillin [ 157 ].…”

Section: Discussionmentioning

confidence: 99%

A Quantitative Survey of Bacterial Persistence in the Presence of Antibiotics: Towards Antipersister Antimicrobial Discovery

Salcedo-Sora

Kell

2020

Antibiotics

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Background: Bacterial persistence to antibiotics relates to the phenotypic ability to survive lethal concentrations of otherwise bactericidal antibiotics. The quantitative nature of the time–kill assay, which is the sector’s standard for the study of antibiotic bacterial persistence, is an invaluable asset for global, unbiased, and cross-species analyses. Methods: We compiled the results of antibiotic persistence from antibiotic-sensitive bacteria during planktonic growth. The data were extracted from a sample of 187 publications over the last 50 years. The antibiotics used in this compilation were also compared in terms of structural similarity to fluorescent molecules known to accumulate in Escherichia coli. Results: We reviewed in detail data from 54 antibiotics and 36 bacterial species. Persistence varies widely as a function of the type of antibiotic (membrane-active antibiotics admit the fewest), the nature of the growth phase and medium (persistence is less common in exponential phase and rich media), and the Gram staining of the target organism (persistence is more common in Gram positives). Some antibiotics bear strong structural similarity to fluorophores known to be taken up by E. coli, potentially allowing competitive assays. Some antibiotics also, paradoxically, seem to allow more persisters at higher antibiotic concentrations. Conclusions: We consolidated an actionable knowledge base to support a rational development of antipersister antimicrobials. Persistence is seen as a step on the pathway to antimicrobial resistance, and we found no organisms that failed to exhibit it. Novel antibiotics need to have antipersister activity. Discovery strategies should include persister-specific approaches that could find antibiotics that preferably target the membrane structure and permeability of slow-growing cells.

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“…Alternatively, this loss of activity could be due to an Eagle effect of PAβN. The phenomenon has been described as a paradoxical effect of drugs where more drug kills less and apparently is not related to solubility 40,41 .…”

Section: Discussionmentioning

confidence: 99%

A permeability-increasing drug synergizes with bacterial efflux pump inhibitors and restores susceptibility to antibiotics in multi-drug resistant Pseudomonas aeruginosa strains

Ferrer‐Espada

Shahrour

Pitts

et al. 2019

Sci Rep

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Resistance to antibiotics poses a major global threat according to the World Health Organization. Restoring the activity of existing drugs is an attractive alternative to address this challenge. One of the most efficient mechanisms of bacterial resistance involves the expression of efflux pump systems capable of expelling antibiotics from the cell. Although there are efflux pump inhibitors (EPIs) available, these molecules are toxic for humans. We hypothesized that permeability-increasing antimicrobial peptides (AMPs) could lower the amount of EPI necessary to sensitize bacteria to antibiotics that are efflux substrates. To test this hypothesis, we measured the ability of polymyxin B nonapeptide (PMBN), to synergize with antibiotics in the presence of EPIs. Assays were performed using planktonic and biofilm-forming cells of Pseudomonas aeruginosa strains overexpressing the MexAB-OprM efflux system. Synergy between PMBN and EPIs boosted azithromycin activity by a factor of 2,133 and sensitized P. aeruginosa to all tested antibiotics. This reduced several orders of magnitude the amount of inhibitor needed for antibiotic sensitization. The selected antibiotic-EPI-PMBN combination caused a 10 million-fold reduction in the viability of biofilm forming cells. We proved that AMPs can synergize with EPIs and that this phenomenon can be exploited to sensitize bacteria to antibiotics.

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Eagle Effect in Nonreplicating Persister Mycobacteria

Cited by 15 publications

References 34 publications

mRNA Degradation Rates Are Coupled to Metabolic Status in Mycobacterium smegmatis

mRNA Degradation Rates Are Coupled to Metabolic Status in Mycobacterium smegmatis

A Quantitative Survey of Bacterial Persistence in the Presence of Antibiotics: Towards Antipersister Antimicrobial Discovery

A permeability-increasing drug synergizes with bacterial efflux pump inhibitors and restores susceptibility to antibiotics in multi-drug resistant Pseudomonas aeruginosa strains

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