<scp>Lon</scp> protease inactivation, or translocation of the <scp><i>lon</i></scp> gene, potentiate bacterial evolution to antibiotic resistance

Nicoloff, Hervé; Andersson, Dan I.

doi:10.1111/mmi.12429

Cited by 53 publications

(45 citation statements)

References 50 publications

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“…It is, therefore, possible that Lon inactivation or, alternatively, a significant down-regulation of the intracellular Lon levels, may have preceded the fixation of the triple mutant. Indeed, inactivation of Lon via insertion of the mobile element IS186 was observed previously in adaptation to other antibiotics (5,27) and in adaptation after orthologous replacement of DHFR (20). Furthermore, a dramatic drop in Lon abundance in response to chromosomal integration of destabilized DHFR mutants has been observed (24).…”

Section: Rodrigues Et Almentioning

confidence: 70%

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Biophysical principles predict fitness landscapes of drug resistance

Rodrigues

Bershtein

et al. 2016

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

156

265

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Fitness landscapes of drug resistance constitute powerful tools to elucidate mutational pathways of antibiotic escape. Here, we developed a predictive biophysics-based fitness landscape of trimethoprim (TMP) resistance for Escherichia coli dihydrofolate reductase (DHFR). We investigated the activity, binding, folding stability, and intracellular abundance for a complete set of combinatorial DHFR mutants made out of three key resistance mutations and extended this analysis to DHFR originated from Chlamydia muridarum and Listeria grayi. We found that the acquisition of TMP resistance via decreased drug affinity is limited by a trade-off in catalytic efficiency. Protein stability is concurrently affected by the resistant mutants, which precludes a precise description of fitness from a single molecular trait. Application of the kinetic flux theory provided an accurate model to predict resistance phenotypes (IC50) quantitatively from a unique combination of the in vitro protein molecular properties. Further, we found that a controlled modulation of the GroEL/ES chaperonins and Lon protease levels affects the intracellular steady-state concentration of DHFR in a mutation-specific manner, whereas IC50 is changed proportionally, as indeed predicted by the model. This unveils a molecular rationale for the pleiotropic role of the protein quality control machinery on the evolution of antibiotic resistance, which, as we illustrate here, may drastically confound the evolutionary outcome. These results provide a comprehensive quantitative genotype–phenotype map for the essential enzyme that serves as an important target of antibiotic and anticancer therapies.

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Section: Rodrigues Et Almentioning

confidence: 70%

“…Inactivation or down-regulation of Lon protease, which effect is shown in Fig. 4, may constitute one such mechanism, and, in fact, has been observed recently during the evolution of strains with orthologous replacements of DHFR (20) and in the evolution of antibiotic resistance (5,27).…”

Section: Deconvolution Of Fitness Into Microlandscapes Shows Strong Ementioning

confidence: 83%

Biophysical principles predict fitness landscapes of drug resistance

Rodrigues

Bershtein

et al. 2016

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

156

265

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“…A previous study also revealed that lon mutants display a 40-50 % increase in acrAB transcription and high MarA levels (Nicoloff et al, 2006). Also, lon mutants confer low antibiotic resistance which is amplified by duplication of acrAB and the abundance of MarA (Nicoloff & Andersson, 2013;Nicoloff et al, 2007). However, other studies did not detect induction of marA and acrAB in lon mutants (Martin et al, 2008;White et al, 1997).…”

Section: Discussionmentioning

confidence: 95%

“…Earlier studies reported that E. coli lon mutants are sensitive to colicin (Lee et al, 2006), doxycycline (Girgis et al, 2009) and plant oils (Shapira & Mimran, 2007), but resistant to several antibiotics and organic solvents (Nicoloff & Andersson, 2013;Nicoloff et al, 2007;Watanabe & Doukyu, 2014). A previous study also revealed that lon mutants display a 40-50 % increase in acrAB transcription and high MarA levels (Nicoloff et al, 2006).…”

Section: Discussionmentioning

confidence: 97%

Roles of Lon protease and its substrate MarA during sodium salicylate-mediated growth reduction and antibiotic resistance in Escherichia coli

et al. 2016

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The cellular proteolytic machinery orchestrates protein turnover and regulates several key biological processes. This study addresses the roles of Lon, a major ATP-dependent protease, in modulating the responses of Escherichia coli strain MG1655 to low and high amounts of sodium salicyclate (NaSal), a widely used clinically relevant analgesic. NaSal affects several bacterial responses, including growth and resistance to multiple antibiotics. The loss of lon reduces growth in response to high, but not low, amounts of NaSal. From amongst a panel of Lon substrates, MarA was identified to be the downstream target of Lon. Thus, stabilization of MarA in the absence of lon lowers growth of the strain in the presence of higher amounts of NaSal. The steady-state transcript levels of marA and its target genes, acrA, acrB and tolC, are higher in the Dlon strain compared with the WT strain. Consequently, the resistance to antibiotics, e.g. tetracycline and nalidixic acid, is enhanced in Dlon in a marA-dependent manner. Furthermore, the target genes of MarA, i.e. acrB and tolC, are responsible for NaSal-mediated antibiotic resistance. Studies using atomic force microscopy demonstrated that ciprofloxacin led to greater cell filamentation, which is lower in the Dlon strain due to higher levels of MarA. Overall, this study delineates the roles of Lon protease, its substrate MarA and downstream targets of MarA, e.g. acrB and tolC, during NaSal-mediated growth reduction and antibiotic resistance. The implications of these observations in the adaptation of E. coli under different environmental conditions are discussed.

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“…In detail, deficiencies in the Lon protease result in the activation of ISs (Nicoloff et al 2007), which might lead to an elevated overall mutation rate in the genome (Chao et al 1983) and a Lon protease deficiency has explicitly been shown to facilitate sequence duplications involving the acrAB locus (Nicoloff and Andersson 2013). A similar function may be expressed by ycbZ , which shows domain homology to the Lon protease (see http://www.uniprot.org/uniprot/C4ZQ81, last accessed May 28, 2014).…”

Section: Discussionmentioning

confidence: 99%

Genomics of Rapid Adaptation to Antibiotics: Convergent Evolution and Scalable Sequence Amplification

Laehnemann

Peña‐Miller

Rosenstiel³

et al. 2014

Genome Biology and Evolution

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Evolutionary adaptation can be extremely fast, especially in response to high selection intensities. A prime example is the surge of antibiotic resistance in bacteria. The genomic underpinnings of such rapid changes may provide information on the genetic processes that enhance fast responses and the particular trait functions under selection. Here, we use experimentally evolved Escherichia coli for a detailed dissection of the genomics of rapid antibiotic resistance evolution. Our new analyses demonstrate that amplification of a sequence region containing several known antibiotic resistance genes represents a fast genomic response mechanism under high antibiotic stress, here exerted by drug combination. In particular, higher dosage of such antibiotic combinations coincided with higher copy number of the sequence region. The amplification appears to be evolutionarily costly, because amplification levels rapidly dropped after removal of the drugs. Our results suggest that amplification is a scalable process, as copy number rapidly changes in response to the selective pressure encountered. Moreover, repeated patterns of convergent evolution were found across the experimentally evolved bacterial populations, including those with lower antibiotic selection intensities. Intriguingly, convergent evolution was identified on different organizational levels, ranging from the above sequence amplification, high variant frequencies in specific genes, prevalence of individual nonsynonymous mutations to the unusual repeated occurrence of a particular synonymous mutation in Glycine codons. We conclude that constrained evolutionary trajectories underlie rapid adaptation to antibiotics. Of the identified genomic changes, sequence amplification seems to represent the most potent, albeit costly genomic response mechanism to high antibiotic stress.

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Lon protease inactivation, or translocation of the lon gene, potentiate bacterial evolution to antibiotic resistance

Cited by 53 publications

References 50 publications

Biophysical principles predict fitness landscapes of drug resistance

Biophysical principles predict fitness landscapes of drug resistance

Roles of Lon protease and its substrate MarA during sodium salicylate-mediated growth reduction and antibiotic resistance in Escherichia coli

Genomics of Rapid Adaptation to Antibiotics: Convergent Evolution and Scalable Sequence Amplification

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