Targeting fundamental pathways to disrupt Staphylococcus aureus survival: clinical implications of recent discoveries

Thomsen, Isaac; Liu, George Y.

doi:10.1172/jci.insight.98216

Cited by 21 publications

(13 citation statements)

References 166 publications

(160 reference statements)

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“…Treatment of S. aureus infections can be difficult due to its antibiotic resistance. Infections caused by methicillin-resistant S. aureus (MRSA) and vancomycin resistant S. aureus (VRSA) have limited treatment options [4–6]. As an alternative strategy, metabolic pathways critical for survival and virulence can be targeted as ways to reduce S. aureus infections and their severity [6].…”

Section: Introductionmentioning

confidence: 99%

Impact of Deficiencies in Branched-Chain Fatty Acids and Staphyloxanthin inStaphylococcus aureus

Braungardt

Singh

2019

BioMed Research International

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Staphylococcus aureus is a well-known human pathogen with the ability to cause mild superficial skin infections to serious deep-tissue infections, such as osteomyelitis, pneumonia, and infective endocarditis. A key to S. aureus infections and its pathogenicity is its ability to survive in adverse environments, especially at lower temperatures, by regulation of its cell membrane. Branched-chain fatty acids (BCFAs) and staphyloxanthin have been shown to regulate membrane fluidity and staphylococcal virulence. This study was conducted with the hypothesis that the simultaneous lack of BCFAs and staphyloxanthin will have a far greater implication on environmental survival and virulence of S. aureus. Lack of a functional branched-chain α-keto acid dehydrogenase (BKD) enzyme because of a mutation in the lpdA gene led to a decrease in the production of BCFAs, membrane fluidity, slower growth, and poor in vivo survival of S. aureus. A mutation in the crtM gene eliminated the production of staphyloxanthin but it did not affect membrane BCFA levels, fluidity, growth, or in vivo survival. A crtM:lpdA double mutant showed much slower growth and attenuation compared to individual mutants. The results of this study suggest that simultaneous targeting of the BCFA and staphyloxanthin biosynthetic pathways can be a strategy to control S. aureus infections.

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Section: Introductionmentioning

confidence: 99%

Impact of Deficiencies in Branched-Chain Fatty Acids and Staphyloxanthin inStaphylococcus aureus

Braungardt

Singh

2019

BioMed Research International

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“…PK is known to be a crucial enzyme that catalyzes the final glycolysis step, which includes a single phosphoryl group transfer from phosphoenolpyruvate to ADP, to produce a molecule of pyruvate and ATP [28]. Recently, it was considered as a "superhub" protein in S. aureus and was found to be essential for staphylococcal growth and biofilm formation [5][6][7]. In vitro studies (Table 2) showed 6-Tris to be a potent Gyr B inhibitor (IC 50 2.1 ± 0.08 µM) with weak inhibitory activity against PK (IC 50 23.2 ± 0.06 µM).…”

Section: In Vitro Assaymentioning

confidence: 99%

“…The limited effectiveness of standard antibiotics in dealing with biofilm-related infections, which increase the emergence of multidrug-resistant staphylococci, together with the increased dependence on implanted medical devices, drives the need for exploring and developing new classes of antimicrobials. Recently, pyruvate kinase (PK) has been identified as a crucial enzyme in staphylococci, and regulates their growth, antibiotic resistance, and biofilm formation [5][6][7]. Furthermore, it was found to be structurally distinct from human homologs, and hence it provides a promising target for novel antimicrobial agents [8,9].…”

Section: Introductionmentioning

confidence: 99%

Discovery of Two Brominated Oxindole Alkaloids as Staphylococcal DNA Gyrase and Pyruvate Kinase Inhibitors via Inverse Virtual Screening

et al. 2020

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In the present study, a small marine-derived natural products library was assessed for antibacterial potential. Among 36 isolated compounds, a number of bis-indole derivatives exhibited growth-inhibitory activity towards Gram-positive strains (Bacillus subtilis and multidrug-resistant Staphylococcus aureus). 5- and 6-trisindoline (5-Tris and 6-Tris) were the most active derivatives (minimum inhibitory concentration, MIC, 4–8 µM) that were subsequently selected for anti-biofilm activity evaluation. Only 5-Tris was able to inhibit the staphylococcal biofilm formation starting at a 5 µM concentration. In order to investigate their possible molecular targets, both natural products were subjected to in silico inverse virtual screening. Among 20 target proteins, DNA gyrase and pyruvate kinase were the most likely to be involved in the observed antibacterial and anti-biofilm activities of both selected natural products. The in vitro validation and in silico binding mode studies revealed that 5-Tris could act as a dual enzyme inhibitor (IC50 11.4 ± 0.03 and 6.6 ± 0.05 µM, respectively), while 6-Tris was a low micromolar gyrase-B inhibitor (IC50 2.1 ± 0.08 µM), indicating that the bromine position plays a crucial role in the determination of the antibacterial lead compound inhibitory activity.

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“…S. aureus is also capable of surviving and thriving in both professional and non-professional phagocytes where it evades immune defences and where antibiotic action is severely limited compared to extracellular forms [6][7][8]. In this context, discovery and development of new chemical or biological entities targeting unexploited but essential targets in S. aureus is of prime importance to evade existing mechanisms of resistance [9].…”

Section: Introductionmentioning

confidence: 99%

Cellular pharmacokinetics and intracellular activity of the bacterial fatty acid synthesis inhibitor, afabicin desphosphono against different resistance phenotypes of Staphylococcus aureus in models of cultured phagocytic cells

Peyrusson

Wessem

Dieppois

et al. 2020

International Journal of Antimicrobial Agents

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Targeting fundamental pathways to disrupt Staphylococcus aureus survival: clinical implications of recent discoveries

Cited by 21 publications

References 166 publications

Impact of Deficiencies in Branched-Chain Fatty Acids and Staphyloxanthin inStaphylococcus aureus

Impact of Deficiencies in Branched-Chain Fatty Acids and Staphyloxanthin inStaphylococcus aureus

Discovery of Two Brominated Oxindole Alkaloids as Staphylococcal DNA Gyrase and Pyruvate Kinase Inhibitors via Inverse Virtual Screening

Cellular pharmacokinetics and intracellular activity of the bacterial fatty acid synthesis inhibitor, afabicin desphosphono against different resistance phenotypes of Staphylococcus aureus in models of cultured phagocytic cells

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