Subinhibitory Concentrations of Bacteriostatic Antibiotics Induce
            <i>relA</i>
            -Dependent and
            <i>relA</i>
            -Independent Tolerance to β-Lactams

Kudrin, Pavel; Varik, Vallo; Oliveira, Sofia Raquel Alves; Beljantseva, Jelena; Santos, Teresa del Peso; Dzhygyr, Ievgen; Rejman, Dominik; Cava, Felipe; Tenson, Tanel; Hauryliuk, Vasili

doi:10.1128/aac.02173-16

Cited by 58 publications

(63 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These strains also showed the induction of relA, as observed following mupirocin treatment (Fig. 6), supporting previous observations that relA upregulation can induce antibiotic tolerance (44,45). Moreover, transcripts related to major cellular functions, such as translation (ribosomal genes), carbohydrate, fat, and energy metabolism, and nucleotide synthesis, were commonly downregulated, while amino acid biosynthesis-and transportation-related operons were upregulated in the R2, R3, and R6 strains, as in mupirocin-treated cells (Fig.…”

Section: Discussionsupporting

confidence: 90%

Genetic and Transcriptomic Analyses of Ciprofloxacin-TolerantStaphylococcus aureusIsolated by the Replica Plating Tolerance Isolation System (REPTIS)

Matsuo

Hiramatsu

Singh

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

We developed a simple, efficient, and cost-effective method, named the replica plating tolerance isolation system (REPTIS), to detect the antibiotic tolerance potential of a bacterial strain. This method can also be used to quantify the antibiotic-tolerant subpopulation in a susceptible population. Using REPTIS, we isolated ciprofloxacin (CPFX)-tolerant mutants (mutants R2, R3, R5, and R6) carrying a total of 12 mutations in 12 different genes from methicillin-sensitive Staphylococcus aureus (MSSA) strain FDA209P. Each mutant carried multiple mutations, while few strains shared the same mutation. The R2 strain carried a nonsense mutation in the stress-mediating gene, relA. Additionally, two strains carried the same point mutation in the leuS gene, encoding leucyl-tRNA synthetase. Furthermore, RNA sequencing of the R strains showed a common upregulation of relA. Overall, transcriptome analysis showed downregulation of genes related to translation; carbohydrate, fat, and energy metabolism; nucleotide synthesis; and upregulation of amino acid biosynthesis and transportation genes in R2, R3, and R6, similar to the findings observed for the FDA209P strain treated with mupirocin (MUP0.03). However, R5 showed a unique transcription pattern that differed from that of MUP0.03. REPTIS is a unique and convenient method for quantifying the level of tolerance of a clinical isolate. Genomic and transcriptomic analyses of R strains demonstrated that CPFX tolerance in these S. aureus mutants occurs via at least two distinct mechanisms, one of which is similar to that which occurs with mupirocin treatment.

show abstract

Section: Discussionsupporting

confidence: 90%

Genetic and Transcriptomic Analyses of Ciprofloxacin-TolerantStaphylococcus aureusIsolated by the Replica Plating Tolerance Isolation System (REPTIS)

Matsuo

Hiramatsu

Singh

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Proteome analysis of erythromycin-exposed "permeable" E. coli suggests a RpoS-regulated profile (45). In fact, sub-inhibitory concentrations of bacteriostatic antibiotics induce the stringent response, leading to beta-lactam tolerance (46).…”

Section: Discussionmentioning

confidence: 99%

Antibiotic killing of diversely generated populations of non-replicating bacteria

Shah

McCall

Govindan

et al. 2018

Preprint

View full text Add to dashboard Cite

Non-replicating bacteria are known to be (or at least commonly thought to be) refractory to antibiotics to which they are genetically susceptible. Here, we explore the sensitivity to killing by bactericidal antibiotics of three classes of non-replicating populations of planktonic bacteria; (1) stationary phase, when the concentration of resources and/or nutrients are too low to allow for population growth; (2) persisters, minority subpopulations of susceptible bacteria surviving exposure to bactericidal antibiotics; (3) antibiotic-static cells, bacteria exposed to antibiotics that prevent their replication but kill them slowly if at all, the so-called bacteriostatic drugs. Using experimental populations of Staphylococcus aureus Newman and Escherichia coli K12 (MG1655) and respectively 9 and 7 different bactericidal antibiotics, we estimate the rates at which these drugs kill these different types of non-replicating bacteria. Contrary to the common belief that bacteria that are non-replicating are refractory to antibiotic-mediated killing, all three types of non-replicating populations of these Gram-positive and Gram-negative bacteria are consistently killed by aminoglycosides and the peptide antibiotics, daptomycin and colistin, respectively. This result indicates that non-replicating cells, irrespectively of why they do not replicate, have an almost identical response to bactericidal antibiotics. We discuss the implications of these results to our understanding of the mechanisms of action of antibiotics and the possibility of adding a short-course of aminoglycosides or peptide antibiotics to conventional therapy of bacterial infections.

show abstract

“…permit antibiotic resistance to evolve more easily, as well as accommodate the emergence of persistor cells that are genotypically equivalent to wild-type bacteria yet physiologically capable of withstanding antibiotic exposure (Kudrin et al, 2017). On the other hand, lytic phage are always bactericidal, lysing cells at the completion of a replication cycle.…”

Section: Perspectives and Future Directions Will Phage Ever Replace Amentioning

confidence: 99%

Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria

Kortright

Chan

Koff

et al. 2019

Cell Host & Microbe

797

585

View full text Add to dashboard Cite

Phage therapy, long overshadowed by chemical antibiotics, is garnering renewed interest in Western medicine. This stems from the rise in frequency of multi-drug-resistant bacterial infections in humans. There also have been recent case reports of phage therapy demonstrating clinical utility in resolving these otherwise intractable infections. Nevertheless, bacteria can readily evolve phage resistance too, making it crucial for modern phage therapy to develop strategies to capitalize on this inevitability. Here, we review the history of phage therapy research. We compare and contrast phage therapy and chemical antibiotics, highlighting their potential synergies when used in combination. We also examine the use of animal models, case studies, and results from clinical trials. Throughout, we explore how the modern scientific community works to improve the reliability and success of phage therapy in the clinic and discuss how to properly evaluate the potential for phage therapy to combat antibiotic-resistant bacteria.

show abstract

Subinhibitory Concentrations of Bacteriostatic Antibiotics Induce relA -Dependent and relA -Independent Tolerance to β-Lactams

Cited by 58 publications

References 96 publications

Genetic and Transcriptomic Analyses of Ciprofloxacin-TolerantStaphylococcus aureusIsolated by the Replica Plating Tolerance Isolation System (REPTIS)

Genetic and Transcriptomic Analyses of Ciprofloxacin-TolerantStaphylococcus aureusIsolated by the Replica Plating Tolerance Isolation System (REPTIS)

Antibiotic killing of diversely generated populations of non-replicating bacteria

Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria

Contact Info

Product

Resources

About