Antibiotic resistance by high-level intrinsic suppression of a frameshift mutation in an essential gene

Huseby, Douglas L.; Brandis, Gerrit; Alzrigat, Lisa Praski; Hughes, Diarmaid

doi:10.1073/pnas.1919390117

Cited by 23 publications

(11 citation statements)

References 41 publications

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“…It has been postulated that both translational frameshifting and the propensity of the DNA replication errors at these sequences aid the cells in antigenic variation and evasion of the host immune system. In M. tuberculosis, some rifampicinresistant strains contain an insertion mutation in rpoB, the b subunit of RNA polymerase (110). This insertion is suppressed by a subsequent translational 11 frameshift that leads to a 3-amino acid change in RpoB, resulting in high levels of rifampicin resistance.…”

Section: Proteome Regulation Through Frameshiftingmentioning

confidence: 99%

Translational regulation of environmental adaptation in bacteria

Tollerson

Ibba

2020

Journal of Biological Chemistry

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Bacteria must rapidly respond to both intracellular and environmental changes to survive. One critical mechanism to rapidly detect and adapt to changes in environmental conditions is control of gene expression at the level of protein synthesis. At each of the three major steps of translation—initiation, elongation, and termination—cells use stimuli to tune translation rate and cellular protein concentrations. For example, changes in nutrient concentrations in the cell can lead to translational responses involving mechanisms such as dynamic folding of riboswitches during translation initiation or the synthesis of alarmones, which drastically alter cell physiology. Moreover, the cell can fine-tune the levels of specific protein products using programmed ribosome pausing or inducing frameshifting. Recent studies have improved understanding and revealed greater complexity regarding longstanding paradigms describing key regulatory steps of translation such as start-site selection and the coupling of transcription and translation. In this review, we describe how bacteria regulate their gene expression at the three translational steps and discuss how translation is used to detect and respond to changes in the cellular environment. Finally, we appraise the costs and benefits of regulation at the translational level in bacteria.

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Section: Proteome Regulation Through Frameshiftingmentioning

confidence: 99%

Translational regulation of environmental adaptation in bacteria

Tollerson

Ibba

2020

Journal of Biological Chemistry

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“…By coupling genetic and proteomic approaches, it was recently shown that frameshifting of the rpoB gene is a mechanism used by pathogenic mycobacteria to generate resistance to antibiotics [ 142 ]. Importantly, LC/MS/MS was applied to demonstrate low levels of frameshift suppression of rpoB mutations, indicating that sometimes, what is encoded in the genome does not necessarily predict the resulting proteome [ 142 ]. The decoupling of the proteome from the genome underscores the necessity of combining approaches that alter the genome and measure the proteome.…”

Section: The Genetic Proteome and Antibiotic Susceptibility And Resismentioning

confidence: 99%

The genetic proteome: Using genetics to inform the proteome of mycobacterial pathogens

et al. 2021

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Mycobacterial pathogens pose a sustained threat to human health. There is a critical need for new diagnostics, therapeutics, and vaccines targeting both tuberculous and nontuberculous mycobacterial species. Understanding the basic mechanisms used by diverse mycobacterial species to cause disease will facilitate efforts to design new approaches toward detection, treatment, and prevention of mycobacterial disease. Molecular, genetic, and biochemical approaches have been widely employed to define fundamental aspects of mycobacterial physiology and virulence. The recent expansion of genetic tools in mycobacteria has further increased the accessibility of forward genetic approaches. Proteomics has also emerged as a powerful approach to further our understanding of diverse mycobacterial species. Detection of large numbers of proteins and their modifications from complex mixtures of mycobacterial proteins is now routine, with efforts of quantification of these datasets becoming more robust. In this review, we discuss the “genetic proteome,” how the power of genetics, molecular biology, and biochemistry informs and amplifies the quality of subsequent analytical approaches and maximizes the potential of hypothesis-driven mycobacterial research. Published proteomics datasets can be used for hypothesis generation and effective post hoc supplementation to experimental data. Overall, we highlight how the integration of proteomics, genetic, molecular, and biochemical approaches can be employed successfully to define fundamental aspects of mycobacterial pathobiology.

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“…It is noteworthy that most of the mutations occurred in membrane proteins whose involvement hasn't been highlighted in this work even though it's logical to assume that the cell membrane would be the first barrier to exogenous isobutanol and its toxicity. The real problem is our incomplete knowledge of the linkages between genome and transcriptome and hence our inability to predict phenotype from changes in the genome sequence 55 .…”

Section: S No Locus_tagmentioning

confidence: 99%

Genomics and transcriptomics analysis reveals the mechanism of isobutanol tolerance of a laboratory evolved Lactococcus lactis strain

Gupta

Thapa

Verma

et al. 2020

Sci Rep

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Isobutanol, in spite of its significant superiority over ethanol as a biofuel, remains commercially non-viable due to the non-availability of a suitable chassis which can handle the solvent toxicity associated with its production. to meet this challenge, we chose Lactococcus lactis which is known for its ability to handle environmental stress and carried out Adaptive laboratory evolution (ALe) in a continuous stirred tank reactor (cStR) to evolve an isobutanol tolerant strain. the strain was grown for more than 60 days (> 250 generations) while gradually increasing the selection pressure, i.e. isobutanol concentration, in the feed. this led to the evolution of a strain that had an exceptionally high tolerance of up to 40 g/l of isobutanol even though a scanning electron microscope (SEM) study as well as analysis of membrane potential revealed only minor changes in cellular morphology. Whole genome sequencing which was done to confirm the strain integrity also showed comparatively few mutations in the evolved strain. However, the criticality of these mutations was reflected in major changes that occurred in the transcriptome, where gene expression levels from a wide range of categories that involved membrane transport, amino acid metabolism, sugar uptake and cell wall synthesis were significantly altered. Analysing the synergistic effect of these changes that lead to the complex phenotype of isobutanol tolerance can help in the construction of better host platforms for isobutanol production. The growing demands for energy in the world economy, coupled with the opposing need to reduce our carbon footprint, has spurred research in the area of biofuels. Thus, major gains have been made in last decade, where systems biology approaches have been successfully combined with metabolic engineering and synthetic biology tools, to engineer microbes to produce advanced biofuels. However, we still have a long way to go before commercial production of these biofuels takes place. This is because of multiple bottlenecks in the process; one of the primary ones being the poor tolerance of these microbes for the product. This feedback inhibition by higher alcohols effectively ensures that the final product titers are so low as to make the production process economically unviable 1. Attempts to engineer solvent tolerance in a host have been mixed bag of success 2. Each organism has its own intrinsic solvent tolerance level, which is genetically determined and environmentally influenced. Therefore, organic solvent tolerance is believed to be a strain-specific property 3,4. The host response to solvent toxicity involves the induction of a complex stress response at the global level. Studies have shown that many strains of Saccharomyces cerevisiae exhibit restricted growth in 20 g/l butanol while lactic acid bacteria (LAB) including Lactobacillus delbrueckii and Lactobacillus brevis can grow in 30 g/l butanol. Strains of Clostridia are unable to tolerate more than 20 g/l butanol while Escherichia coli and Zymomonas mobilis strains showe...

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Antibiotic resistance by high-level intrinsic suppression of a frameshift mutation in an essential gene

Cited by 23 publications

References 41 publications

Translational regulation of environmental adaptation in bacteria

Translational regulation of environmental adaptation in bacteria

The genetic proteome: Using genetics to inform the proteome of mycobacterial pathogens

Genomics and transcriptomics analysis reveals the mechanism of isobutanol tolerance of a laboratory evolved Lactococcus lactis strain

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