Gausemycins†A,B: Cyclic Lipoglycopeptides from Streptomyces sp.*.

We report a novel family of natural lipoglycopeptides produced by Streptomyces sp. INA-Ac-5812. Two major components of the mixture, named gausemycins A and B, were isolated, and their structures were elucidated. The compounds are cyclic peptides with a unique peptide core and several remarkable structural features, including unusual positions of d-amino acids, lack of the Ca2+ -binding Asp-X-Asp-Gly (DXDG) motif, tyrosine glycosylation with arabinose, presence of 2-amino-4-hydroxy-4-phenylbutyric acid (Ahpb) and chlorinated kynurenine (ClKyn), and N-acylation of the ornithine side chain. Gausemycins have pronounced activity against Gram-positive bacteria. Mechanistic studies highlight significant differences compared to known glyco- and lipopeptides. Gausemycins exhibit only slight Ca2+ -dependence of activity and induce no pore formation at low concentrations. Moreover, there is no detectable accumulation of cell wall biosynthesis precursors under treatment with gausemycins.

Polypharmacological drug actions of recently FDA approved antibiotics.

The current epidemic of antibiotic resistant bacterial infections has fueled the demand for novel antibiotics exhibiting both antibacterial efficacy and anti-drug resistance. This need has not been fully satisfied by the conventional "one target-one molecule" approach. Consequently, there has been rising interest in the development of multi-target antibiotics. Over the past two decades, 52% (14 out of 27) of the FDA approved antibiotics have demonstrated synergistic, multi-target mechanisms of action. Among these are three second-generation lipoglycopeptides, five new generation quinolones and six modernized ß-lactams. This review focuses on the structure-activity relationship (SAR) analysis and the polypharmacological drug action of these antibiotics, to reveal how these multi-target antibiotics achieve the dual objectives of maximizing bactericidal or bacteriostatic efficacy and minimizing antibiotic resistance. The entrance of multi-target antibiotics into the FDA-approved regimens represents a milestone in the evolution of drug discovery as it has transcended from chemical library screening to rational drug design.

Advantages of Outpatient Treatment with Long-Acting Lipoglycopeptides for Serious Gram-Positive Infections: A Review.

Treatment of serious gram-positive infections presents multiple challenges. Treatment often results in prolonged hospitalization for administration of intravenous antimicrobials and presents an inefficient use of hospital resources. Prolonged hospitalization is typically also unfavorable to patient preferences and potentially subjects patients to additional health care-associated complications. Current strategies of transition to outpatient settings-outpatient parenteral antimicrobial therapy and use of oral antibiotics-often do not adequately serve vulnerable populations for whom there is often no alternative to inpatient therapy. Specifically, people who use drugs, those who cannot reliably adhere to unsupervised treatment (poor mental or physical health), people with complicating life circumstances (e.g., homelessness, incarceration, rural location), and those with inadequate health insurance remain hospitalized for weeks longer than persons without such conditions. We suspected that long-acting lipoglycopeptides (laLGP), such as dalbavancin and oritavancin, may be useful in patient transitions to outpatient settings. Thus, we conducted a search of the peer-reviewed literature using the PubMed, Google Scholar, and MEDLINE databases. Based on accumulating literature, it appears that laLGPs offer a reliable alternative therapeutic strategy that addresses many of the personal and systemic barriers to the traditional transitioning approaches. Current evidence also suggests that these agents may be cost-effective from patient, payer, and hospital perspectives. Barriers to broader use of laLGPs include, among others, a relative lack of prospective data regarding efficacy in serious infections, a narrow United States Food and Drug Administration-approved indication restricted to only acute bacterial skin and skin structure infections, and lack of reimbursement infrastructure for inpatient settings.

Fluorescence assay to predict activity of the glycopeptide antibiotics.

Here, we describe a fluorescent assay developed to study competitive binding of the glycopeptide antibiotics to live bacteria cells. This assay demonstrated that the mechanism of action of the lipoglycopeptide antibiotics strongly depends on the hydrophobicity of the substitutes, with the best antibacterial activity of the glycopeptide antibiotics equally sharing properties of binding to D-Ala-D-Ala residues of the nascent peptidoglycan and to the membrane.

Effects of Microplate Type and Broth Additives on Microdilution MIC Susceptibility Assays.

The determination of antibiotic potency against bacterial strains by assessment of their minimum inhibitory concentration normally uses a standardized broth microdilution assay procedure developed more than 50 years ago. However, certain antibiotics require modified assay conditions in order to observe optimal activity. For example, daptomycin requires medium supplemented with Ca2+, and the lipoglycopeptides dalbavancin and oritavancin require Tween 80 to be added to the growth medium to prevent the depletion of free drug via adsorption to the plastic microplate. In this report, we examine systematically the effects of several different plate types on microdilution broth MIC values for a set of antibiotics against Gram-positive and Gram-negative bacteria, both in medium alone and in medium supplemented with the commonly used additives Tween 80, lysed horse blood, and 50% human serum. We observed very significant differences in measured MICs (up to 100-fold) for some lipophilic antibiotics, such as the Gram-positive lipoglycopeptide dalbavancin and the Gram-negative lipopeptide polymyxins, and found that nonspecific binding plates can replace the need for surfactant additives. Microtiter plate types and any additives should be specified when reporting broth dilution MIC values, as results can vary dramatically for some classes of antibiotics.

Treasures from the Deep: Characellides as Anti-Inflammatory Lipoglycotripeptides from the Sponge Characella pachastrelloides.

The chemical investigation of marine invertebrates from the deep Northeastern Atlantic revealed new lipoglycotripeptides named characellides isolated from the tetractinellid sponge Characella pachastrelloides. This new family of natural products features a central tripeptide linked to a rare sugar unit and a long alkyl chain ending with a 2,3-dimethyltetrahydropyran. The configurations of all 13 chiral centers were determined by extensive use of NMR data and circular dichroism spectra combined with calculations.

Clinical Pharmacokinetics and Pharmacodynamics of Telavancin Compared with the Other Glycopeptides.

Telavancin was discovered by modifying the chemical structure of vancomycin and belongs to the group of lipoglycopeptides. It employs its antimicrobial potential through two distinct mechanisms of action: inhibition of bacterial cell wall synthesis and induction of bacterial membrane depolarization and permeabilization. In this article we review the clinically relevant pharmacokinetic and pharmacodynamic data of telavancin. For comparison, the pharmacokinetic and pharmacodynamic data of the other glycopeptides are presented. Although, in contrast to the newer lipoglycopeptides, telavancin demonstrates a relatively short half-life and rapid total clearance, its apparent volume of distribution (Vd) is almost identical to that of dalbavancin. The accumulation of telavancin after repeated dosing is only marginal, whereas the pharmacokinetic values of the other glycopeptides show much greater differences after administration of multiple doses. Despite its high plasma-protein binding of 90% and relatively low Vd of approximately 11 L, telavancin shows near complete equilibration of the free fraction in plasma with soft tissue. The ratio of the area under the plasma concentration-time curve from time zero to 24 h (AUC24) of unbound plasma concentrations to the minimal inhibitory concentration (MIC) required to inhibit growth of 90% of organisms (MIC90) of Staphylococcus aureus and S. epidermidis of telavancin are sufficiently high to achieve pharmacokinetic/pharmacodynamic targets indicative for optimal bacterial killing. Considering both the AUC24/MIC ratios of telavancin and the near complete equilibration of the free fraction in plasma with soft tissue, telavancin is an appropriate antimicrobial agent to treat soft tissue infections caused by Gram-positive pathogens. Although the penetration of telavancin into epithelial lining fluid (ELF) requires further investigations, the AUC24/MIC ratio for S. aureus indicates that bactericidal activity in the ELF could be expected.