Consequences of daptomycin-mediated membrane damage in Staphylococcus aureus

Hobbs, Joanne K.; Miller, Keith; O’Neill, Alex J.; Chopra, Ian

doi:10.1093/jac/dkn321

Cited by 122 publications

(110 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These findings suggest that these novel compounds can be used as lead compounds for the development of antimicrobial agents. The potent inhibition of macromolecule synthesis and rapid bactericidal activity of compounds 1 and 3 suggested that they, like daptomycin 18 and XF-73, 19 might damage bacterial membranes. Further experiments are required to gain more insight into the exact mechanism of action of these novel compounds.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel deoxyribofuranosyl indole antimicrobial agents

et al. 2011

View full text Add to dashboard Cite

Three novel deoxyribofuranosyl indole derivatives, FG050227 (1), FG050223 (2) and FG050204 (3), were identified as antimicrobial agents effective against Gram-positive bacterial strains and some fungi. The MIC values of (1), (2) and (3) against methicillin-resistant Staphylococcus aureus were 3.0, 6.0 and 13 lg ml À1 , respectively. Compounds 1 and 3 had bactericidal activity against exponentially growing S. aureus and inhibited biosynthesis of peptidoglycan, protein, RNA and DNA. Compound 2 was bacteriostatic and inhibited the biosynthesis of protein and RNA. The results indicated that deoxyribofuranosyl indole derivatives could be potential lead compounds for the development of antimicrobial agents. The Journal of Antibiotics (2012) 65, 53-57; doi:10.1038/ja.2011; published online 14 December 2011Keywords: bactericidal; macromolecule synthesis; MRSA; novel antimicrobial; VRE INTRODUCTIONThe emergence of resistant strains against antimicrobial agents is a serious problem in the clinical field. Staphylococcus aureus strains resistant to penicillin 1 and methicillin 2 were identified as early as 2 years after their initial use. Vancomycin-resistant enterococcus (VRE) emerged in 1987, 3 a few years after vancomycin began to be used worldwide. 4 S. aureus that is resistant to relatively intermediate concentrations of vancomycin was first reported in 1997 in Japan. 5 Linezolide and daptomycin, the antibiotics effective against methicillin-resistant Staphylococcus aures (MRSA) and VRE, became ineffective within 1 6 and 2 7,8 years after approval by Food and Drug Administration in the USA, respectively. Therefore, the discovery of novel antimicrobial agents effective against multi-drug resistant bacteria is crucial. Toward this aim, we screened chemical compounds against S. aureus. Here, we report the identification of three novel deoxyribofuranosyl indole compounds as potential antimicrobial agents against Gram-positive bacteria, including MRSA and VRE, and some fungi. MATERIALS AND METHODS Microbial strains and culture conditionsThe bacterial and fungal strains used in this study are summarized in Table 1. Bacterial cultures were prepared in either Luria Bertani (LB) medium (tryptone 10 g l À1 , yeast extract 5 g l À1 , NaCl 10 g l À1 ) or Muller-Hinton Broth (MHB) (DIFCO, Franklin Lakes, NJ, USA). For antimicrobial susceptibility tests, cation-adjusted MHB was used. Fungal suspensions were prepared in Roswell Park Memorial Institute medium (Sigma Aldrich, St Louis, MO, USA). Chemicals and antibioticsVancomycin, daptomycin and norfloxacin were purchased from Wako Pure Chemicals (Osaka, Japan), Sequoia Research Products (Pangbourne, UK), and Sigma Aldrich, respectively. Rifampicin and chloramphenicol were obtained from Nacalai Tesque (Kyoto, Japan). Radiolabelled Chemical library and screening methodOur chemical library contains intermediates of several natural product synthesis projects, (for example, K252a, 9 ecteinascidin 743, 10 kainic acid, 11 etc). The compounds were screened based on MIC values against meth...

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of novel deoxyribofuranosyl indole antimicrobial agents

et al. 2011

View full text Add to dashboard Cite

show abstract

“…78 These efflux systems are driven by ion gradients or ATP, both of which vanish when daptomycin takes effect. 79 This suggests that penetration of the dye may measure the cell's residual metabolic capacity for powering efflux rather than membrane continuity. Similar considerations may apply to Sytox Green, which like ethidium and propidium is an organic, aromatic cation with affinity for DNA.…”

Section: Functional Size and Solute Specificity Of The Membrane Defectmentioning

confidence: 99%

“…79 ATP regeneration by oxidative phosphorylation will stall when the membrane potential collapses, and moreover the loss of cellular Mg 2+ , which normally stabilizes ATP, should also contribute to ATP depletion. The depletion of amino acids due to the failure of active uptake 75 was already noted earlier (see section 10.4).…”

Section: Depletion Of Substrates and Metabolic Energymentioning

confidence: 99%

“…82 Similarly, Hobbs et al found that the synthetic pathways for DNA, RNA, protein and peptidoglycan all become simultaneously inhibited, and that this inhibition occurs on a similar time scale to the loss of ATP. 79 From the above observations, the question naturally arises whether membrane permeabilization also controls the time course of bactericidal action. While this question was answered in the affirmative by Silverman et al, 73 Hobbs et al maintain that the loss of cell viability precedes that of biosynthetic capacity.…”

Section: Depletion Of Substrates and Metabolic Energymentioning

confidence: 99%

“…However, their reported kinetics of cell killing and biosynthetic collapse differ only by some minutes. 79 Moreover, since daptomycin is tightly bound to the cell membrane, 59 its effect will not be promptly terminated by dilution, and thus the time course of its bactericidal action cannot be accurately determined. Therefore, no substantial evidence contradicts the tenet that indeed membrane permeabilization sets the pace for bactericidal action.…”

Section: Depletion Of Substrates and Metabolic Energymentioning

confidence: 99%

See 2 more Smart Citations

The action mechanism of daptomycin

Taylor

Palmer

2016

Bioorganic & Medicinal Chemistry

208

168

View full text Add to dashboard Cite

Daptomycin is a lipopeptide antibiotic produced by the soil bacterium Streptomyces roseosporus that is clinically used to treat severe infections with Grampositive bacteria. In this review, we discuss the mode of action of this important antibiotic. Although daptomycin is structurally related to amphomycin and similar lipopeptides that inhibit peptidoglycan biosynthesis, experimental studies have not produced clear evidence that daptomycin shares their action mechanism. Instead, the best characterized effect of daptomycin is the permeabilization and depolarization of the bacterial cell membrane. This activity, which can account for daptomycin's bactericidal effect, correlates with the level of phosphatidylglycerol (PG) in the membrane. Accordingly, reduced synthesis of PG or its increased conversion to lysyl-PG promotes bacterial resistance to daptomycin. While other resistance mechanisms suggest that daptomycin may indeed directly interfere with cell wall synthesis or cell division, such effects still await direct experimental confirmation. Daptomycin's complex structure and biosynthesis have hampered the analysis of its structure activity relationships. Novel methods of total synthesis, including a recent one that is carried out entirely on a solid phase, will enable a more thorough and systematic exploration of the sequence space.

show abstract

Macromolecular Synthesis and Membrane Perturbation Assays for Mechanisms of Action Studies of Antimicrobial Agents

King

2009

CP Pharmacology

View full text Add to dashboard Cite

The definition and confirmation of the mechanism of action of an NCE is central to antimicrobial drug discovery. Most antibiotics currently in clinical use selectively target and block one or more bacterial macromolecular synthesis processes, e.g., DNA replication, RNA synthesis (transcription), protein synthesis (translation), cell wall (peptidoglycan) synthesis, and fatty acid (lipid) biosynthesis. This unit includes two protocols for determining the effect of test compounds on macromolecular synthesis, one in test tube format and the other in 96-well plate format. A membrane potential depolarization protocol is also provided. Disruption of cell membrane integrity may be a legitimate mechanism of action for antibacterials, but it also may be the result of nonspecific cell membrane activity, an effect that must be ruled out for mammalian cells. These assays provide useful means for verifying inhibition of an intended target pathway with investigational antimicrobial compounds. They can also be used as valuable secondary assays for lead optimization to eliminate inhibitors that display nonselective toxicity.

show abstract

Consequences of daptomycin-mediated membrane damage in Staphylococcus aureus

Cited by 122 publications

References 25 publications

Identification of novel deoxyribofuranosyl indole antimicrobial agents

Identification of novel deoxyribofuranosyl indole antimicrobial agents

The action mechanism of daptomycin

Macromolecular Synthesis and Membrane Perturbation Assays for Mechanisms of Action Studies of Antimicrobial Agents

Contact Info

Product

Resources

About