Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria.

Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1)-ones, exemplified by , that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens.

Application of Virtual Screening to the Identification of New LpxC Inhibitor Chemotypes, Oxazolidinone and Isoxazoline.

This report summarizes the identification and synthesis of novel LpxC inhibitors aided by computational methods that leveraged numerous crystal structures. This effort led to the identification of oxazolidinone and isoxazoline inhibitors with potent in vitro activity against P. aeruginosa and other Gram-negative bacteria.

Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity.

In the preceding manuscript [ Moreau et al. 2018 , 10.1021/acs.

Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria.

The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria are a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria.

Optimization of CoaD Inhibitors against Gram-Negative Organisms through Targeted Metabolomics.

Drug-resistant Gram-negative bacteria are of increasing concern worldwide. Novel antibiotics are needed, but their development is complicated by the requirement to simultaneously optimize molecules for target affinity and cellular potency, which can result in divergent structure-activity relationships (SARs). These challenges were exemplified during our attempts to optimize inhibitors of the bacterial enzyme CoaD originally identified through a biochemical screen.

Synthesis of ciprofloxacin dimers for evaluation of bacterial permeability in atypical chemical space.

We describe the synthesis and evaluation of a library of variably-linked ciprofloxacin dimers. These structures unify and expand on the use of fluoroquinolones as probes throughout the antibiotic literature. A dimeric analog (19) showed enhanced inhibition of its intracellular target (DNA gyrase), and translation to antibacterial activity in whole cells was demonstrated.

Studies on the mechanism of telavancin decreased susceptibility in a laboratory-derived mutant.

Telavancin is a novel semisynthetic lipoglycopeptide derivative of vancomycin with a dual mode of action. This study sought to understand the mechanisms of decreased telavancin susceptibility in a laboratory-derived Staphlococcus aureus mutant Tlv(DS)MED1952. There were extensive changes in the transcriptome of Tlv(DS)MED1952 compared to the susceptible parent strain MED1951.

In vitro activity of telavancin and occurrence of vancomycin heteroresistance in isolates from patients enrolled in phase 3 clinical trials of hospital-acquired pneumonia.

In phase 3 studies of the efficacy of telavancin for the treatment of hospital-acquired pneumonia, 704 Gram-positive and 627 Gram-negative aerobic bacterial pathogens were obtained at baseline from 1503 patients. The majority of Gram-positive isolates (n = 650 [92%]) were Staphylococcus aureus, of which 410 (63%) were methicillin-resistant (MRSA). Of the MRSA isolates, 9.

Further insights into the mode of action of the lipoglycopeptide telavancin through global gene expression studies.

Telavancin is a novel semisynthetic lipoglycopeptide derivative of vancomycin with a decylaminoethyl side chain that is active against Gram-positive bacteria, including Staphylococcus aureus strains resistant to methicillin or vancomycin. A dual mechanism of action has been proposed for telavancin involving inhibition of peptidoglycan biosynthesis and membrane depolarization. Here we report the results of genome-wide transcriptional profiling of the response of S.

Antistaphylococcal activity of TD-1792, a multivalent glycopeptide-cephalosporin antibiotic.

TD-1792 is a new multivalent glycopeptide-cephalosporin antibiotic with potent activity against Gram-positive bacteria. The in vitro activity of TD-1792 was tested against 527 Staphylococcus aureus isolates, including multidrug-resistant isolates. TD-1792 was highly active against methicillin-susceptible S.

In vitro activity of telavancin and comparator antimicrobial agents against a panel of genetically defined staphylococci.

The in vitro activity of telavancin was determined for 94 diverse Staphylococcus spp. Telavancin had MIC(90) values of 0.5 μg/mL for methicillin-susceptible, methicillin-resistant, and vancomycin-susceptible Staphylococcus aureus, and coagulase-negative staphylococci isolates.

In vitro activity of telavancin against Gram-positive isolates from complicated skin and skin structure infections: results from 2 phase 3 (ATLAS) clinical studies.

During phase 3 clinical studies of telavancin for treatment of complicated skin and skin structure infections, a total of 1530 aerobic Gram-positive isolates were identified at baseline. The majority of these strains were Staphylococcus aureus (n = 1214; 62% methicillin-resistant). All isolates were inhibited by ≤ 1 μg/mL of telavancin.

Specificity of induction of the vanA and vanB operons in vancomycin-resistant enterococci by telavancin.

Telavancin is a bactericidal, semisynthetic lipoglycopeptide indicated in the United States for the treatment of complicated skin and skin structure infections caused by susceptible gram-positive bacteria and is under investigation as a once-daily treatment for nosocomial pneumonia. The related vanA and vanB gene clusters mediate acquired resistance to glycopeptides in enterococci by remodeling the dipeptide termini of peptidoglycan precursors from D-alanyl-D-alanine (D-Ala-D-Ala) to D-alanyl-D-lactate (D-Ala-D-Lac). In this study, we assessed the ability of telavancin to induce the expression of van genes in VanA- and VanB-type strains of vancomycin-resistant enterococci.

Fluorescence microscopy demonstrates enhanced targeting of telavancin to the division septum of Staphylococcus aureus.

The cellular binding patterns of fluorescent conjugates of telavancin and vancomycin were evaluated in Staphylococcus aureus by fluorescence microscopy and ratio imaging analysis. Telavancin showed enhanced binding at the division septum compared to vancomycin. This result is consistent with observations that telavancin binds with higher affinity to lipid II than to d-Ala-d-Ala residues in the cell wall, thus demonstrating the preferential binding of telavancin to the site of active cell wall biosynthesis.

Activity of telavancin against heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) in vitro and in an in vivo mouse model of bacteraemia.

Objectives: Infections caused by heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) are associated with high rates of vancomycin treatment failure. Telavancin is a bactericidal lipoglycopeptide active in vitro against Gram-positive pathogens including hVISA and vancomycin-intermediate S. aureus (VISA).

Telavancin disrupts the functional integrity of the bacterial membrane through targeted interaction with the cell wall precursor lipid II.

Telavancin is an investigational lipoglycopeptide antibiotic currently being developed for the treatment of serious infections caused by gram-positive bacteria. The bactericidal action of telavancin results from a mechanism that combines the inhibition of cell wall synthesis and the disruption of membrane barrier function. The purpose of the present study was to further elucidate the mechanism by which telavancin interacts with the bacterial membrane.

In vitro activity of telavancin against resistant gram-positive bacteria.

The in vitro activity of telavancin was tested against 743 predominantly antimicrobial-resistant, gram-positive isolates. Telavancin was highly active against methicillin-resistant staphylococci (MIC(90), 0.5 to 1 microg/ml), streptococci (all MICs, < or =0.

Comparative surveillance study of telavancin activity against recently collected gram-positive clinical isolates from across the United States.

Telavancin is an investigational, rapidly bactericidal lipoglycopeptide antibiotic that is being developed to treat serious infections caused by gram-positive bacteria. A baseline prospective surveillance study was conducted to assess telavancin activity, in comparison with other agents, against contemporary clinical isolates collected from 2004 to 2005 from across the United States. Nearly 4,000 isolates were collected, including staphylococci, enterococci, and streptococci (pneumococci, beta-hemolytic, and viridans).

In vitro activity of telavancin against recent Gram-positive clinical isolates: results of the 2004-05 Prospective European Surveillance Initiative.

Objectives: Telavancin is a novel semi-synthetic lipoglycopeptide currently in late-stage clinical development for the treatment of serious infections due to Gram-positive bacteria. The objective of this study was to provide a baseline prospective assessment of its in vitro activity against a large and diverse collection of Gram-positive clinical isolates from Europe and Israel.

Methods: Gram-positive clinical isolates, collected between October 2004 and December 2005 from 36 hospital laboratories in 15 countries, were tested by broth microdilution using CLSI methodology.

Intrapulmonary distribution of intravenous telavancin in healthy subjects and effect of pulmonary surfactant on in vitro activities of telavancin and other antibiotics.

Steady-state concentrations of telavancin, a novel, bactericidal lipoglycopeptide, were determined in the plasma, pulmonary epithelial lining fluid (ELF), and alveolar macrophages (AMs) of 20 healthy subjects. Telavancin at 10 mg of drug/kg of body weight/day was administered as a 1-h intravenous infusion on three successive days, with bronchoalveolar lavage performed on five subjects, each at 4, 8, 12, and 24 h after the last dose. Plasma samples were collected before the first and third infusions and at 1, 2, 3, 4, 8, 12, and 24 h after the third infusion.

Efficacy of telavancin in a murine model of bacteraemia induced by methicillin-resistant Staphylococcus aureus.

Objectives: The efficacy of telavancin, a bactericidal lipoglycopeptide, was compared with vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) in an immunocompromised murine model of bacteraemia.

Methods: Immunocompromised mice were inoculated intraperitoneally with S. aureus ATCC 33591 and treated with two subcutaneous doses (once every 12 h) of vehicle or test compound.

Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus.

The emergence and spread of multidrug-resistant gram-positive bacteria represent a serious clinical problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clinically relevant gram-positive pathogens. Here we demonstrate that telavancin's antibacterial activity derives from at least two mechanisms.

Large-scale identification of genes required for full virulence of Staphylococcus aureus.

Gene products required for in vivo growth and survival of microbial pathogens comprise a unique functional class and may represent new targets for antimicrobial chemotherapy, vaccine construction, or diagnostics. Although some factors governing Staphylococcus aureus pathogenicity have been identified and studied, a comprehensive genomic analysis of virulence functions will be a prerequisite for developing a global understanding of interactions between this pathogen and its human host. In this study, we describe a genetic screening strategy and demonstrate its use in screening a collection of 6,300 S.