scholarly journals Genetically Engineered Lipopeptide Antibiotics Related to A54145 and Daptomycin with Improved Properties

2010 ◽  
Vol 54 (4) ◽  
pp. 1404-1413 ◽  
Author(s):  
Kien T. Nguyen ◽  
Xiaowei He ◽  
Dylan C. Alexander ◽  
Chen Li ◽  
Jian-Qiao Gu ◽  
...  
Keyword(s):  
Community Acquired Pneumonia ◽  
Genetically Engineered ◽  
Combinatorial Biosynthesis ◽  
Gram Positive ◽  
Cyclic Lipopeptide ◽  
Highly Active ◽  
Hybrid Molecules ◽  
Methyltransferase Gene ◽  
Lipopeptide Antibiotic

ABSTRACT Daptomycin is a cyclic lipopeptide antibiotic approved for the treatment of skin and skin structure infections caused by Gram-positive pathogens and for that of bacteremia and right-sided endocarditis caused by Staphylococcus aureus. Daptomycin failed to meet noninferiority criteria for the treatment of community-acquired pneumonia, likely due to sequestration in pulmonary surfactant. Many analogues of daptomycin have been generated by combinatorial biosynthesis, but only two displayed improved activity in the presence of bovine surfactant, and neither was as active as daptomycin in vitro. In the present study, we generated hybrid molecules of the structurally related lipopeptide A54145 in Streptomyces fradiae and tested them for antibacterial activity in the presence of bovine surfactant. Hybrid A54145 nonribosomal peptide synthetase (NRPS) biosynthetic genes were constructed by genetic engineering and were expressed in combination with a deletion of the lptI methyltransferase gene, which is involved in the formation of the 3-methyl-glutamic acid (3mGlu) residue at position 12. Some of the compounds were very active against S. aureus and other Gram-positive pathogens; one compound was also highly active in the presence of bovine surfactant, had low acute toxicity, and showed some efficacy against Streptococcus pneumoniae in a mouse model of pulmonary infection.

scholarly journals More Than a Pore: A Current Perspective on the In Vivo Mode of Action of the Lipopeptide Antibiotic Daptomycin

Antibiotics ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 17 ◽  
Author(s):  
Declan Alan Gray ◽  
Michaela Wenzel
Keyword(s):  
Current Knowledge ◽  
Gram Positive ◽  
Resistance Development ◽  
Gram Positive Bacteria ◽  
Cyclic Lipopeptide ◽  
Current Perspective ◽  
Complicated Skin ◽  
Lipopeptide Antibiotic

Daptomycin is a cyclic lipopeptide antibiotic, which was discovered in 1987 and entered the market in 2003. To date, it serves as last resort antibiotic to treat complicated skin infections, bacteremia, and right-sided endocarditis caused by Gram-positive pathogens, most prominently methicillin-resistant Staphylococcus aureus. Daptomycin was the last representative of a novel antibiotic class that was introduced to the clinic. It is also one of the few membrane-active compounds that can be applied systemically. While membrane-active antibiotics have long been limited to topical applications and were generally excluded from systemic drug development, they promise slower resistance development than many classical drugs that target single proteins. The success of daptomycin together with the emergence of more and more multi-resistant superbugs attracted renewed interest in this compound class. Studying daptomycin as a pioneering systemic membrane-active compound might help to pave the way for future membrane-targeting antibiotics. However, more than 30 years after its discovery, the exact mechanism of action of daptomycin is still debated. In particular, there is a prominent discrepancy between in vivo and in vitro studies. In this review, we discuss the current knowledge on the mechanism of daptomycin against Gram-positive bacteria and try to offer explanations for these conflicting observations.

scholarly journals In Vitro Activities of Daptomycin, Vancomycin, Quinupristin- Dalfopristin, Linezolid, and Five Other Antimicrobials against 307 Gram-Positive Anaerobic and 31 Corynebacterium Clinical Isolates

2003 ◽  
Vol 47 (1) ◽  
pp. 337-341 ◽  
Author(s):  
Ellie J. C. Goldstein ◽  
Diane M. Citron ◽  
C. Vreni Merriam ◽  
Yumi A. Warren ◽  
Kerrin L. Tyrrell ◽  
...  
Keyword(s):  
Anaerobic Bacteria ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Gram Positive ◽  
Cyclic Lipopeptide ◽  
Highly Active ◽  
Mueller Hinton Agar ◽  
Vancomycin Resistant ◽  
Corynebacterium Pseudodiphtheriticum

ABSTRACT The activities of daptomycin, a cyclic lipopeptide, and eight other agents were determined against 338 strains of gram-positive anaerobic bacteria and corynebacteria by the NCCLS reference agar dilution method with supplemented brucella agar for the anaerobes and Mueller-Hinton agar for the corynebacteria. The daptomycin MICs determined on Ca2+-supplemented (50 mg/liter) brucella agar plates were one- to fourfold lower than those determined in unsupplemented media. Daptomycin was highly active (MICs, ≤2 μg/ml) against many strains including 36 of 37 peptostreptococci, 37 of 48 isolates of the Eubacterium group, and all strains of Propionibacterium spp., Clostridium perfringens, Clostridium difficile, and other Clostridium spp. It was fourfold or greater more active than vancomycin against Clostridium innocuum and 16 of 34 strains of vancomycin-resistant lactobacilli. Three strains of C. difficile for which quinupristin-dalfopristin and linezolid MICs were >8 μg/ml were inhibited by <1 μg of daptomycin per ml. Daptomycin MICs were ≥4 μg/ml for most strains of Clostridium clostridioforme, Clostridium paraputrificum, Clostridium tertium, and Clostridium ramosum; the isolates were generally more resistant to other antimicrobials. Daptomycin was two- to fourfold less active against Actinomyces spp. than vancomycin, quinupristin-dalfopristin, or linezolid. Twenty-nine of 31 strains of Corynebacterium spp., including Corynebacterium jeikeium, Corynebacterium amycolatum, and Corynebacterium pseudodiphtheriticum, were inhibited by ≤0.25 μg of daptomycin per ml. For two strains of “Corynebacterium aquaticum,” 8 μg of daptomycin per ml was required for inhibition. Daptomycin demonstrated very good activities against a broad range of gram-positive organisms including vancomycin-resistant C. innocuum and lactobacillus strains and quinupristin-dalfopristin- and linezolid-resistant C. difficile strains.

scholarly journals In Vitro Activity of Ceftazidime-Avibactam against Isolates from Respiratory and Blood Specimens from Patients with Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia, in a Phase 3 Clinical Trial

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Gregory G. Stone ◽  
Patricia A. Bradford ◽  
Margaret Tawadrous ◽  
Dianna Taylor ◽  
Mary Jane Cadatal ◽  
...  
Keyword(s):  
Nosocomial Pneumonia ◽  
Bacterial Pathogen ◽  
Multidrug Resistant ◽  
Ventilator Associated Pneumonia ◽  
Phase 3 ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type ◽  
Highly Active

ABSTRACT Nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), is increasingly associated with multidrug-resistant Gram-negative pathogens. This study describes the in vitro activity of ceftazidime-avibactam, ceftazidime, and relevant comparator agents against bacterial pathogens isolated from patients with NP, including VAP, enrolled in a ceftazidime-avibactam phase 3 trial. Gram-positive pathogens were included if coisolated with a Gram-negative pathogen. In vitro susceptibility was determined at a central laboratory using Clinical and Laboratory Standards Institute broth microdilution methods. Of 817 randomized patients, 457 (55.9%) had ≥1 Gram-negative bacterial pathogen(s) isolated at baseline, and 149 (18.2%) had ≥1 Gram-positive pathogen(s) coisolated. The most common isolated pathogens were Klebsiella pneumoniae (18.8%), Pseudomonas aeruginosa (15.8%), and Staphylococcus aureus (11.5%). Ceftazidime-avibactam was highly active in vitro against 370 isolates of Enterobacteriaceae, with 98.6% susceptible (MIC90, 0.5 μg/ml) compared with 73.2% susceptible for ceftazidime (MIC90, >64 μg/ml). The percent susceptibility values for ceftazidime-avibactam and ceftazidime against 129 P. aeruginosa isolates were 88.4% and 72.9% (MIC90 values of 16 μg/ml and 64 μg/ml), respectively. Among ceftazidime-nonsusceptible Gram-negative isolates, ceftazidime-avibactam percent susceptibility values were 94.9% for 99 Enterobacteriaceae and 60.0% for 35 P. aeruginosa. MIC90 values for linezolid and vancomycin (permitted per protocol for Gram-positive coverage) were within their respective MIC susceptibility breakpoints against the Gram-positive pathogens isolated. This analysis demonstrates that ceftazidime-avibactam was active in vitro against the majority of Enterobacteriaceae and P. aeruginosa isolates from patients with NP, including VAP, in a phase 3 trial. (This study has been registered at ClinicalTrials.gov under identifier NCT01808092.)

scholarly journals Bactericidal Activities of Two Daptomycin Regimens against Clinical Strains of Glycopeptide Intermediate-ResistantStaphylococcus aureus, Vancomycin-ResistantEnterococcus faecium, and Methicillin-ResistantStaphylococcus aureus Isolates in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations

2001 ◽  
Vol 45 (2) ◽  
pp. 454-459 ◽  
Author(s):  
Ronda L. Akins ◽  
Michael J. Rybak
Keyword(s):  
Limit Of Detection ◽  
Infection Model ◽  
Infection Site ◽  
Gram Positive ◽  
Killing Effect ◽  
Vancomycin Resistant ◽  
Cell Membrane Transport ◽  
Bactericidal Activities ◽  
Lipopeptide Antibiotic

ABSTRACT Daptomycin is an investigational lipopeptide antibiotic active against gram-positive organisms. The mechanism of action is unique, resulting in interference with cell membrane transport. The bactericidal activity of daptomycin was evaluated against glycopeptide-intermediate susceptible Staphylococcus aureus(GISA), vancomycin-resistant Enterococcus faecium (VREF), and methicillin-resistant S. aureus (MRSA) in an in vitro infection model with simulated endocardial vegetations. Simulated regimens of daptomycin at 6 mg/kg/day (D6) and 10 mg/kg/day (D10) were utilized. MICs and MBCs for daptomycin were determined in the absence and in the presence of albumin with the following results (MIC/MBC): for GISA-992, 0.5/1.0 and 16/16; for VREF-590, 2.0/2.0 and 32/32; and for MRSA-494, 0.25/0.25 and 1.0/4.0 μg/ml, respectively. During the first 8 h daptomycin significantly reduced the inoculum for all organisms. Daptomycin at 6 mg/kg/day and 10 mg/kg/day had log10 CFU/g reductions of 5 and 6, 3.4 and 5, and 6.4 and 6.5 by 8 h for GISA-992, VREF-590, and MRSA-494, respectively. Against both GISA-992 and VREF-590, the D10 regimen achieved the limit of detection at 72 h, with D6 regimens showing slight regrowth. A concentration-dependent killing effect was noted to occur, with daptomycin demonstrating a more rapid and greater kill from the D10 versus the D6 regimen. The results of this study suggest that daptomycin demonstrates significant (P < 0.05) activity against gram-positive organisms in a simulated sequestered infection site.

scholarly journals Activity of New Synthetic (2-Chloroethylthio)-1,4-naphthoquinones in Prostate Cancer Cells

2021 ◽  
Vol 14 (10) ◽  
pp. 949
Author(s):  
Sergey A. Dyshlovoy ◽  
Dmitry N. Pelageev ◽  
Lea S. Jakob ◽  
Ksenia L. Borisova ◽  
Jessica Hauschild ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Parp Inhibitor ◽  
Dependent Manner ◽  
Akt Inhibitor ◽  
Anticancer Properties ◽  
Highly Active ◽  
Development Of Resistance ◽  
Castration Resistant ◽  
Hybrid Molecules

Development of resistance to currently available standard therapies in advanced prostate cancer (PCa) emphasizes the need for novel therapeutic options. Here, we report the synthesis of new hybrid molecules consisting of 2-chloroethylthio and 1,4-naphthoquinone pharmacophores and describe their activity in PCa. In screening analyses, the introduction of one 2-chloroethylthio group improved the anticancer properties of 1,4-naphthoquinones, whereas the introduction of a second 2-chloroethylthio moiety rather decreased activity. Two most promising of the synthesized compounds, 30 and 32, were highly active in different human PCa cell lines harboring varying resistance profiles at nanomolar concentrations. The generated data suggest that the compounds are capable of mitochondria targeting, cytotoxic ROS induction, and DNA damage, which resulted in apoptosis presumably executed in a caspase-dependent manner. The substances synergized with the clinically approved PARP inhibitor olaparib and resensitized AR-V7-expressing PCa cells to antiandrogen enzalutamide, as well as to a combination of enzalutamide and an AKT inhibitor. This was at least in part exerted via down-regulation of AR-V7 expression and inhibition of AR signaling. Mild antagonism was observed in combination with platinum- or taxane-based chemotherapy, which was putatively related to treatment-induced activation of p38, JNK1/2, ERK1/2, MEK1/2, and AKT, functioning as potential pro-survival factors. Thus, the synthesized (2-chloroethylthio)-1,4-naphthoquinone derivatives exhibit promising anticancer properties in vitro, suggesting their further development as potential therapeutics for the treatment of castration-resistant PCa.

scholarly journals In Vitro Activity of Telavancin against Resistant Gram-Positive Bacteria

2008 ◽  
Vol 52 (7) ◽  
pp. 2647-2652 ◽  
Author(s):  
Kevin M. Krause ◽  
Marika Renelli ◽  
Stacey Difuntorum ◽  
Terry X. Wu ◽  
Dmitri V. Debabov ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Gram Positive Bacteria ◽  
Highly Active ◽  
Time Kill

ABSTRACT The in vitro activity of telavancin was tested against 743 predominantly antimicrobial-resistant, gram-positive isolates. Telavancin was highly active against methicillin-resistant staphylococci (MIC90, 0.5 to 1 μg/ml), streptococci (all MICs, ≤0.12 μg/ml), and VanB-type enterococci (all MICs, ≤2 μg/ml). Time-kill studies demonstrated the potent bactericidal activity of telavancin.

scholarly journals Antimicrobial Properties of MX-2401, an Expanded-Spectrum Lipopeptide Active in the Presence of Lung Surfactant

2011 ◽  
Vol 55 (8) ◽  
pp. 3720-3728 ◽  
Author(s):  
Dominique Dugourd ◽  
Haiyan Yang ◽  
Melissa Elliott ◽  
Raymond Siu ◽  
Jacob J. Clement ◽  
...  
Keyword(s):  
Lung Surfactant ◽  
Antimicrobial Properties ◽  
Coagulase Negative Staphylococci ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Gram Positive Bacteria ◽  
Lipopeptide Antibiotic ◽  
Hospital Acquired

ABSTRACTMX-2401 is an expanded-spectrum lipopeptide antibiotic selective for Gram-positive bacteria that is a semisynthetic analog of the naturally occurring lipopeptide amphomycin. It was active againstEnterococcusspp., including vancomycin-sensitiveEnterococcus(VSE),vanA-,vanB-, andvanC-positive vancomycin-resistantEnterococcus(VRE), linezolid- and quinupristin-dalfopristin-resistant isolates (MIC90of 4 μg/ml), methicillin-resistantStaphylococcus aureus(MRSA) and methicillin-sensitiveS. aureus(MSSA) (MIC90of 2 μg/ml), coagulase-negative staphylococci, including methicillin-sensitiveStaphylococcus epidermidis(MSSE) and methicillin-resistantS. epidermidis(MRSE) (MIC90of 2 μg/ml), andStreptococcusspp. including viridans group streptococci, and penicillin-resistant, penicillin-sensitive, penicillin-intermediate and macrolide-resistant isolates ofStreptococcus pneumoniae(MIC90of 2 μg/ml). MX-2401 demonstrated a dose-dependent postantibiotic effect varying from 1.5 to 2.4 h. Furthermore, MX-2401 was rapidly bactericidal at 4 times the MIC againstS. aureusandEnterococcus faecalis, with more than 99.9% reduction in viable bacterial attained at 4 and 24 h, respectively. The MICs of MX-2401 against MRSA, MSSA, VSE, and VRE strains serially exposed for 15 passages to sub- to supra-MICs of MX-2401 remained within three dilutions of the original MIC. In contrast to that of the lipopeptide daptomycin, the antibacterial activity of MX-2401 was not affectedin vitroby the presence of lung surfactant, and MX-2401 was activein vivoin the bronchial-alveolar pneumonia mouse model, in which daptomycin failed to show any activity. Moreover, the activity of MX-2401 was not as strongly dependent on the Ca2+concentration as is the activity of daptomycin. In conclusion, MX-2401 is a promising new-generation lipopeptide for the treatment of serious infections with Gram-positive bacteria, including hospital-acquired pneumonia.

Sign in / Sign up

Export Citation Format

Share Document