Modulation of Biofilm Growth by Sub‐Inhibitory Amounts of Antibacterial Substances

Stoitsova, Stoyanka; Paunova-Krasteva, Tsvetelina; Borisova, Denitsa

doi:10.5772/62939

Cited by 16 publications

(10 citation statements)

References 90 publications

(114 reference statements)

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“…Biofilm persistence and viability were assessed with the hit compounds in combination with an antibiotic. It has been previously determined that sub-MICs of antibiotics result in increased biofilm formation [ 69 ]. Additionally, it has been previously demonstrated that the starvation response mediates high biofilm specific tolerance to antibiotics [ 70 ].…”

Section: Resultsmentioning

confidence: 99%

The Development of a Pipeline for the Identification and Validation of Small-Molecule RelA Inhibitors for Use as Anti-Biofilm Drugs

et al. 2020

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Biofilm infections have no approved effective medical treatments and can only be disrupted via physical means. This means that any biofilm infection that is not addressable surgically can never be eliminated and can only be managed as a chronic disease. Therefore, there is an urgent need for the development of new classes of drugs that can target the metabolic mechanisms within biofilms which render them recalcitrant to traditional antibiotics. Persister cells within the biofilm structure may play a large role in the enhanced antibiotic recalcitrance of bacteria biofilms. Biofilm persister cells can be resistant to up to 1000 times the minimal inhibitory concentrations of many antibiotics, as compared to their planktonic envirovars; they are thought to be the prokaryotic equivalent of metazoan stem cells. Their metabolic resistance has been demonstrated to be an active process induced by the stringent response that is triggered by the ribosomally-associated enzyme RelA in response to amino acid starvation. This 84-kD pyrophosphokinase produces the “magic spot” alarmones, collectively called (p)ppGpp. These alarmones act by directly regulating transcription by binding to RNA polymerase. These transcriptional changes lead to a major shift in cellular function to both upregulate oxidative stress-combating enzymes and down regulate major cellular functions associated with growth and replication. These changes in gene expression produce the quiescent persister cells. In this work, we describe a hybrid in silico laboratory pipeline for identifying and validating small-molecule inhibitors of RelA for use in the combinatorial treatment of bacterial biofilms as re-potentiators of classical antibiotics.

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Section: Resultsmentioning

confidence: 99%

The Development of a Pipeline for the Identification and Validation of Small-Molecule RelA Inhibitors for Use as Anti-Biofilm Drugs

et al. 2020

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“…In our case, sub-MICs of ASK2 prevented K. pneumoniae biofilm formation suggesting that ASK2 does not trigger (or inhibits) the expression of certain virulence genes that favor biofilm formation. For example sub-MICs of ampicillin increased biofilm growth of Staphylococcus saprophyticus , similarly ciprofloxacin promoted biofilm of S. saprophyticus and E. coli UTI8 (Stoitsova et al, 2016 ). From previous reports we understood that effect of sub-MICs on biofilm varied with type of antibiotics and bacterial species (Stoitsova et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

ASK2 Bioactive Compound Inhibits MDR Klebsiella pneumoniae by Antibiofilm Activity, Modulating Macrophage Cytokines and Opsonophagocytosis

Cheepurupalli

Raman

Rathore

et al. 2017

Front. Cell. Infect. Microbiol.

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The emergence and spread of pathogens harboring extended spectrum beta-lactamase (ESBL) like carbapenem resistant Gram negative bacteria are the major emerging threat to public health. Of particular concern Klebsiella pneumoniae carbapenamase- producing strains have been recorded worldwide. Catheter associated urinary tract infections (CAUTI) caused by K. pneumoniae are significantly associated with morbidity and mortality. Hence the present work was aimed to develop a strategy for addressing these issues through an innovative approach of antibiofilm and immunomodulation. These two independent activities were analyzed in a Streptomyces derived ASK2 bioactive compound. While analysing the effect of sub-minimum inhibitory concentrations (sub-MICs), 0.5x of Minimum Inhibitory Concentration (MIC) was found to be more effective in preventing biofilm formation on coverslip and silicone catheter. The minimum biofilm eradication concentration (MBEC) was found to be 15-fold higher MIC with eradication of 75% of 3 day old biofilm. Apart from its antibiofilm potential, ASK2 also acts as an opsonin and enhances phagocytic response of macrophages against multidrug resistant K. pneumoniae. In addition, ASK2 resulted in elevated levels of nitric oxide generation by the macrophages and has a stimulating effect on IL-12, IFN-γ, and TNF-α proinflammatory cytokines. The opsonic role of ASK2 and its potential in modulating proinflammatory cytokines secreted by macrophages implies the importance of ASK2 in modulating cellular immune response of macrophages against MDR K. pneumoniae. The present study proposes ASK2 as a promising candidate for treating MDR K. pneumoniae infections with its dual properties of antibiofilm and immunomodulatory activities.

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“…It has been determined that sub-MICs of antibiotic result in increased biofilm formation (66). Ampicillin was used in all of our assays due to its bactericidal effect.…”

Section: Effect Of Compound On Biofilm Persistence and Biofilm Viabilitymentioning

confidence: 99%

The Development of a Pipeline for the Identification and Validation of Small-Molecule RelA Inhibitors for Use as Anti-biofilm Drugs

Hall

Król

Cahill

et al. 2020

Preprint

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Biofilm infections have no effective medical treatments and can only be disrupted via physical means. This means that any biofilm infection that is not addressable surgically can never be eliminated and can only be managed as a chronic disease. Therefore, there is an urgent need for the development of new classes of drugs that can target the metabolic mechanisms within biofilms which render them recalcitrant to traditional antibiotics. This antibiotic recalcitrance of bacterial biofilms can be attributed largely to the formation of persister cells within the biofilm structure. These biofilm persister cells can be resistant to up to 1000 times the minimal inhibitory concentrations of many antibiotics as compared to their planktonic envirovars; they are thought to be the prokaryotic equivalent of metazoan stem cells. Their metabolic resistance has been demonstrated to be an active process induced by the stringent response that is triggered by the ribosomally-associated enzyme RelA in response to amino acid starvation. This 84-kD pyrophosphokinase produces the “magic spot” alarmones, collectively called (p)ppGpp. These alarmones act by directly regulating transcription by binding to RNA polymerase. These transcriptional changes lead to a major shift in cellular function to both upregulate oxidative stress-combating enzymes and down regulate major cellular functions associated with growth and replication. These changes in gene expression produce the quiescent persister cells. In this work, we describe a hybrid in silico-laboratory pipeline for identifying and validating small-molecule inhibitors of RelA for use in the combinatorial treatment of bacterial biofilms as re-potentiators of classical antibiotics.

show abstract

Modulation of Biofilm Growth by Sub‐Inhibitory Amounts of Antibacterial Substances

Cited by 16 publications

References 90 publications

The Development of a Pipeline for the Identification and Validation of Small-Molecule RelA Inhibitors for Use as Anti-Biofilm Drugs

The Development of a Pipeline for the Identification and Validation of Small-Molecule RelA Inhibitors for Use as Anti-Biofilm Drugs

ASK2 Bioactive Compound Inhibits MDR Klebsiella pneumoniae by Antibiofilm Activity, Modulating Macrophage Cytokines and Opsonophagocytosis

The Development of a Pipeline for the Identification and Validation of Small-Molecule RelA Inhibitors for Use as Anti-biofilm Drugs

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