Estimated pKa values for specific amino acid residues in daptomycin

Qiu, Jiang; Yu, Liping; Kirsch, Lee E.

doi:10.1002/jps.22608

Cited by 24 publications

(17 citation statements)

References 26 publications

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“…The result suggests a biphasic binding involving strong interactions including electrostatic interactions, hydrogen bond, π stacking, and perhaps covalent interactions, as well as weak interactions such as hydrophobic interactions. 35 Additionally, Dap is a cyclic lipopeptide (13-mer) 36 having an isoelectric point (p I ) of ∼3.8, 37 and has been found to aggregate via a pH-dependent reversible “self-association” mechanism. 38 The increase in loading capacity at low pH is attributable to self-association of Dap.…”

Section: Resultsmentioning

confidence: 99%

Synergistic Photothermal and Antibiotic Killing of Biofilm-Associated Staphylococcus aureus Using Targeted Antibiotic-Loaded Gold Nanoconstructs

et al. 2016

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Resistance to conventional antibiotics is a growing public health concern that is quickly outpacing the development of new antibiotics. This has led the Infectious Diseases Society of America (IDSA) to designate Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species as “ESKAPE pathogens” on the basis of the rapidly decreasing availability of useful antibiotics. This emphasizes the urgent need for alternative therapeutic strategies to combat infections caused by these and other bacterial pathogens. In this study, we used Staphylococcus aureus (S. aureus) as a proof-of-principle ESKAPE pathogen to demonstrate that an appropriate antibiotic (daptomycin) can be incorporated into polydopamine-coated gold nanocages (AuNC@PDA) and that daptomycin-loaded AuNC@PDA can be conjugated to antibodies targeting a species-specific surface protein (staphylococcal protein A; Spa) as a means of achieving selective delivery of the nanoconstructs directly to the bacterial cell surface. Targeting specificity was confirmed by demonstrating a lack of binding to mammalian cells, reduced photothermal and antibiotic killing of the Spa-negative species Staphylococcus epidermidis, and reduced killing of S. aureus in the presence of unconjugated anti-Spa antibodies. We demonstrate that laser irradiation at levels within the current safety standard for use in humans can be used to achieve both a lethal photothermal effect and controlled release of the antibiotic, thus resulting in a degree of therapeutic synergy capable of eradicating viable S. aureus cells. The system was validated using planktonic bacterial cultures of both methicillin-sensitive and methicillin-resistant S. aureus strains and subsequently shown to be effective in the context of an established biofilm, thus indicating that this approach could be used to facilitate the effective treatment of intrinsically resistant biofilm infections.

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Section: Resultsmentioning

confidence: 99%

Synergistic Photothermal and Antibiotic Killing of Biofilm-Associated Staphylococcus aureus Using Targeted Antibiotic-Loaded Gold Nanoconstructs

et al. 2016

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“…With multiple ionizable side‐chain residues, ionization states, and net charge of daptomycin varying with pH, daptomycin aggregation is predicted to be sensitive to both pH and substrate concentration. The sequence‐specific p K a values for the four acidic residues and one aromatic amine (Kyn‐13) in daptomycin were determined by 2D TOCSY NMR pH titration . The estimated p K a values for Asp‐3, Asp‐7, Asp‐9, mGlu‐12, and Kyn‐13 were determined to be 4.3, 1.0, 3.8, 4.6, and 1.3 in aqueous solution.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Lipopeptide (Daptomycin) Aggregation Using Fluorescence, Light Scattering, and Nuclear Magnetic Resonance Spectroscopy

Qiu

Kirsch

2014

Journal of Pharmaceutical Sciences

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“…The pK a values of these residues in the absence of Ca 2+ have been characterized by potentiometric titration, ultraviolet (UV) spectrophotometry, and NMR spectroscopy. 34,35 At physiological pH, all residues except Kyn (13) will be ionized; accordingly, daptomycin with no calcium bound (apo-daptomycin) exists primarily as a trianion. It may be noted that the pK a value for Asp (7) is very low; the exact reason is not clear from the available structural information.…”

Section: Ionization Statementioning

confidence: 99%

The action mechanism of daptomycin

Taylor

Palmer

2016

Bioorganic & Medicinal Chemistry

220

172

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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.

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Estimated pKa values for specific amino acid residues in daptomycin

Cited by 24 publications

References 26 publications

Synergistic Photothermal and Antibiotic Killing of Biofilm-Associated Staphylococcus aureus Using Targeted Antibiotic-Loaded Gold Nanoconstructs

Synergistic Photothermal and Antibiotic Killing of Biofilm-Associated Staphylococcus aureus Using Targeted Antibiotic-Loaded Gold Nanoconstructs

Evaluation of Lipopeptide (Daptomycin) Aggregation Using Fluorescence, Light Scattering, and Nuclear Magnetic Resonance Spectroscopy

The action mechanism of daptomycin

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