31 results on '"Moeck, Greg"'
Search Results
2. Pooled analysis of single-dose oritavancin in the treatment of acute bacterial skin and skin-structure infections caused by Gram-positive pathogens, including a large patient subset with methicillin-resistant Staphylococcus aureus
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Corey, G. Ralph, Arhin, Francis F., Wikler, Matthew A., Sahm, Daniel F., Kreiswirth, Barry N., Mediavilla, José R., Good, Samantha, Fiset, Claude, Jiang, Hai, Moeck, Greg, Kabler, Heidi, Green, Sinikka, and O'Riordan, William
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- 2016
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3. Single-Dose Oritavancin Versus 7–10 Days of Vancomycin in the Treatment of Gram-Positive Acute Bacterial Skin and Skin Structure Infections: The SOLO II Noninferiority Study
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SOLO II Investigators, Corey, G. Ralph, Good, Samantha, Jiang, Hai, Moeck, Greg, Wikler, Matthew, Green, Sinikka, Manos, Paul, Keech, Richard, Singh, Rajesh, Heller, Barry, Bubnova, Natalia, and O'Riordan, William
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- 2015
4. Comparative in vitro activity of oritavancin and other agents against vancomycin-susceptible and -resistant enterococci
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Sweeney, Debora, Stoneburner, Audrey, Shinabarger, Dean L., Arhin, Francis F., Belley, Adam, Moeck, Greg, and Pillar, Chris M.
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- 2017
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5. Supplement to: Single-dose oritavancin in the treatment of acute bacterial skin infections.
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Corey, Ralph G., Kabler, Heidi, Mehra, Purvi, Gupta, Sandeep, Overcash, Scott J., Porwal, Ashwin, Giordano, Philip, Lucasti, Christopher, Perez, Antonio, Good, Samantha, Jiang, Hai, Moeck, Greg, and OʼRiordan, William
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- 2014
6. Dalbavancin or Oritavancin for Skin Infections
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Corey, Ralph G., Jiang, Hai, and Moeck, Greg
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- 2014
7. Single-Dose Oritavancin in the Treatment of Acute Bacterial Skin Infections
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Corey, G. Ralph, Kabler, Heidi, Mehra, Purvi, Gupta, Sandeep, Overcash, J. Scott, Porwal, Ashwin, Giordano, Philip, Lucasti, Christopher, Perez, Antonio, Good, Samantha, Jiang, Hai, Moeck, Greg, and OʼRiordan, William
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- 2014
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8. A new class of small molecule RNA polymerase inhibitors with activity against Rifampicin-resistant Staphylococcus aureus
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Arhin, Francis, Bélanger, Odette, Ciblat, Stéphane, Dehbi, Mohammed, Delorme, Daniel, Dietrich, Evelyne, Dixit, Dilip, Lafontaine, Yanick, Lehoux, Dario, Liu, Jing, McKay, Geoffrey A., Moeck, Greg, Reddy, Ranga, Rose, Yannick, Srikumar, Ramakrishnan, Tanaka, Kelly S.E., Williams, Daniel M., Gros, Philippe, Pelletier, Jerry, Parr, Thomas R., Jr., and Far, Adel Rafai
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- 2006
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9. Competition of bacteriophage polypeptides with native replicase proteins for binding to the DNA sliding clamp reveals a novel mechanism for DNA replication arrest in Staphylococcus aureus
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Belley, Adam, Callejo, Mario, Arhin, Francis, Dehbi, Mohammed, Fadhil, Ibtihal, Liu, Jing, McKay, Geoffrey, Srikumar, Ramakrishnan, Bauda, Pascale, Ha, Nhuan, DuBow, Michael, Gros, Philippe, Pelletier, Jerry, and Moeck, Greg
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- 2006
10. Single-Dose Oritavancin Versus 7–10 Days of Vancomycin in the Treatment of Gram-Positive Acute Bacterial Skin and Skin Structure Infections: The SOLO II Noninferiority Study.
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Corey, G. Ralph, Good, Samantha, Jiang, Hai, Moeck, Greg, Wikler, Matthew, Green, Sinikka, Manos, Paul, Keech, Richard, Singh, Rajesh, Heller, Barry, Bubnova, Natalia, and O'Riordan, William
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GRAM-positive bacterial infections ,METHICILLIN-resistant staphylococcus aureus treatment ,VANCOMYCIN ,TREATMENT effectiveness ,PHARMACOKINETICS ,BACTERIAL disease treatment - Abstract
A single 1200-mg dose of oritavancin was noninferior to 7–10 days of vancomycin for treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by gram-positive pathogens. Oritavancin provides a single-dose alternative to multi-dose therapies for ABSSSI.Background. Oritavancin is a lipoglycopeptide antibiotic with rapid bactericidal activity against gram-positive bacteria. Its concentration-dependent activity and long half-life allow for single-dose treatment.Methods. In a randomized, double-blind trial, adults with acute bacterial skin and skin structure infections (ABSSSIs) received either a single intravenous 1200-mg dose of oritavancin or 7–10 days of twice-daily vancomycin. Three efficacy endpoints were tested for noninferiority: (1) primary composite endpoint at 48–72 hours (cessation of spreading or reduction in lesion size, absence of fever, and no rescue antibiotic); (2) investigator-assessed clinical cure 7–14 days after end of treatment; and (3) ≥20% reduction in lesion area at 48–72 hours.Results. A total of 503 and 502 patients comprised the modified intent-to-treat population for oritavancin and vancomycin, respectively. All 3 efficacy endpoints met the 10% noninferiority margin: the primary composite endpoint (80.1% vs 82.9%; 95% confidence interval [CI], −7.5 to 2.0), investigator-assessed clinical cure (82.7% vs 80.5%; 95% CI, −2.6 to 7.0), and proportion of patients attaining ≥20% reduction in lesion area (85.9% vs 85.3%; 95% CI, −3.7 to 5.0) for oritavancin vs vancomycin, respectively. Efficacy outcomes by pathogen, including methicillin-resistant Staphylococcus aureus and the frequency of adverse events, were similar between treatment groups.Conclusions. A single 1200-mg dose of oritavancin was noninferior to 7–10 days of vancomycin in treating ABSSSIs caused by gram-positive pathogens, and was well tolerated. Oritavancin provides a single-dose alternative to multidose therapies for the treatment of ABSSSIs.Clinical Trials Registration. NCT01252732. [ABSTRACT FROM PUBLISHER]
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- 2015
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11. Triaminotriazine DNA helicase inhibitors with antibacterial activity
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McKay, Geoffrey A., Reddy, Ranga, Arhin, Francis, Belley, Adam, Lehoux, Dario, Moeck, Greg, Sarmiento, Ingrid, Parr, Thomas R., Gros, Philippe, Pelletier, Jerry, and Far, Adel Rafai
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- 2006
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12. Antimicrobial drug discovery through bacteriophage genomics.
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Arhin, Francis, Bauda, Pascale, Bergeron, Dominique, Callejo, Mario, Ferretti, Vincent, Nhuan Ha, Vincent, Kwan, Tony, McCarty, John, Srikumar, Ramakrishnan, Williams, Dan, Jinzi J. Wu, Dan, Gros, Philippe, Pelletier, Jerry, DuBow, Michael, Jing Liu, Dehbi, Mohammed, and Moeck, Greg
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ANTI-infective agents ,BACTERIOPHAGE genetics ,ANTIBIOTICS ,GENETICS of staphylococcus aureus infections ,DNA replication ,COMMUNICABLE diseases - Abstract
Over evolutionary time bacteriophages have developed unique proteins that arrest critical cellular processes to commit bacterial host metabolism to phage reproduction. Here, we apply this concept of phage-mediated bacterial growth inhibition to antibiotic discovery. We sequenced 26 Staphylococcus aureus phages and identified 31 novel polypeptide families that inhibited growth upon expression in S. aureus. The cellular targets for some of these polypeptides were identified and several were shown to be essential components of the host DNA replication and transcription machineries. The interaction between a prototypic pair, ORF104 of phage 77 and DnaI, the putative helicase loader of S. aureus, was then used to screen for small molecule inhibitors. Several compounds were subsequently found to inhibit both bacterial growth and DNA synthesis. Our results suggest that mimicking the growth-inhibitory effect of phage polypeptides by a chemical compound, coupled with the plethora of phages on earth, will yield new antibiotics to combat infectious diseases. [ABSTRACT FROM AUTHOR]
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- 2004
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13. Cefepime--Taniborbactam in Complicated Urinary Tract Infection.
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Wagenlehner, Florian M., Gasink, Leanne B., McGovern, Paul C., Moeck, Greg, McLeroth, Patrick, Dorr, MaryBeth, Dane, Aaron, and Henkel, Tim
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URINARY tract infections , *CEFEPIME , *GRAM-negative bacteria , *PSEUDOMONAS aeruginosa - Abstract
BACKGROUND Carbapenem-resistant Enterobacterales species and multidrug-resistant Pseudomonas aeruginosa are global health threats. Cefepime-taniborbactam is an investigational β-lactam and β-lactamase inhibitor combination with activity against Enterobacterales species and P. aeruginosa expressing serine- and metallo-j8-lactamases. METHODS In this phase 3, double-blind, randomized trial, we assigned hospitalized adults with complicated urinary tract infection (UTI), including acute pyelonephritis, in a 2:1 ratio to receive intravenous cefepime-taniborbactam (2.5 g) or meropenem (1 g) every 8 hours for 7 days; this duration could be extended up to 14 days in case of bacteremia. The primary outcome was both microbiologie and clinical success (composite success) on trial days 19 to 23 in the microbiologie intention-to-treat (microITT) population (patients who had a qualifying gram-negative pathogen against which both study drugs were active). A prespecified superiority analysis of the primary outcome was performed after confirmation of noninferiority. RESULTS Of the 661 patients who underwent randomization, 436 (66.0%) were included in the microITT population. The mean age of the patients was 56.2 years, and 38.1% were 65 years of age or older. In the microITT population, 57.8% of the patients had complicated UTI, 42.2% had acute pyelonephritis, and 13.1% had bacteremia. Composite success occurred in 207 of 293 patients (70.6%) in the cefepime-taniborbactam group and in 83 of 143 patients (58.0%) in the meropenem group. Cefepime-taniborbactam was superior to meropenem regarding the primary outcome (treatment difference, 12.6 percentage points; 95% confidence interval, 3.1 to 22.2; P = 0.009). Differences in treatment response were sustained at late follow-up (trial days 28 to 35), when cefepime-taniborbactam had higher composite success and clinical success. Adverse events occurred in 35.5% and 29.0% of patients in the cefepime-taniborbactam group and the meropenem group, respectively, with headache, diarrhea, constipation, hypertension, and nausea the most frequently reported; the frequency of serious adverse events was similar in the two groups. CONCLUSIONS Cefepime-taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem. (Funded by Venatorx Pharmaceuticals and others; CERTAIN-1 ClinicalTrials.gov number, NCT03840148.) [ABSTRACT FROM AUTHOR]
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- 2024
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14. A Real-world Patient Registry for Oritavancin Demonstrates Efficacy and Safety Consistent With the Phase 3 SOLO Program.
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Redell, Mark, Moeck, Greg, Lucasti, Christopher, Durso, Stephanie, Kennedy, Cynthia, Fusaro, Karen, Loutit, Jeff, and Dudley, Michael
- Abstract
Background Oritavancin is a lipoglycopeptide used in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in adults. To characterize its use in patients in the postapproval setting, a patient registry was developed. Methods Data collected in an ongoing retrospective observational registry are used to evaluate the utilization, outcomes, and adverse events (AEs) associated with oritavancin for the treatment of infections presumed or confirmed to be caused by gram-positive (GP) bacteria in clinical practice. Results Data for 112 patients from 8 sites were collected. All patients received a single 1200-mg dose of oritavancin mostly in an infusion center. Infection type included cellulitis (67.0%), cutaneous abscess (21.4%), and wound (4.5%). Most patients (72.3%) received 1 or more antimicrobial agents for the index GP infection within 28 days prior to oritavancin treatment. Of positive cultures obtained prior to oritavancin administration, methicillin-resistant Staphylococcus aureus was the predominant pathogen (78.4%). A positive clinical response was observed in 92.8% of patients, and microbial eradication was observed in 90.0% of patients with post-therapy cultures. Within 28 days following oritavancin administration, 4 (3.6%) patients were hospitalized for failure of treatment of the index infection. Five (4.5%) patients experienced 1 or more possible drug-related AEs, which were consistent with types previously reported. There were no drug-related serious AEs reported. Conclusions Clinical and microbiologic outcomes and safety of single-dose oritavancin 1200 mg were similar in this older patient population with multiple comorbid conditions to those observed in the phase 3 SOLO trials. [ABSTRACT FROM AUTHOR]
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- 2018
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15. Genome Annotation and Intraviral Interactome for the Streptococcus pneumoniae Virulent Phage Dp-1.
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Sabri, Mourad, Häuser, Roman, Ouellette, Marc, Liu, Jing, Dehbi, Mohammed, Moeck, Greg, García, Ernesto, Titz, Björn, Uetz, Peter, and Moineau, Sylvain
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GENOMES , *STREPTOCOCCUS pneumoniae , *BACTERIOPHAGES , *PROTEINS , *PROTEIN-protein interactions - Abstract
Streptococcus pneumoniae causes several diseases, including pneumonia, septicemia, and meningitis. Phage Dp-1 is one of the very few isolated virulent S. pneumoniae bacteriophages, but only a partial characterization is currently available. Here, we confirmed that Dp-1 belongs to the family Siphoviridae. Then, we determined its complete genomic sequence of 56,506 bp. It encodes 72 open reading frames, of which 44 have been assigned a function. We have identified putative promoters, Rho-independent terminators, and several genomic clusters. We provide evidence that Dp-1 may be using a novel DNA replication system as well as redirecting host protein synthesis through queuosine-containing tRNAs. Liquid chromatography-mass spectrometry analysis of purified phage Dp-1 particles identified at least eight structural proteins. Finally, using comprehensive yeast two-hybrid screens, we identified 156 phage protein interactions, and this intraviral interactome was used to propose a structural model of Dp-1. [ABSTRACT FROM AUTHOR]
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- 2011
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16. ARGONAUT-III and -V: susceptibility of carbapenem-resistant Klebsiella pneumoniae and multidrug-resistant Pseudomonas aeruginosa to the bicyclic boronate β-lactamase inhibitor taniborbactam combined with cefepime.
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Jacobs MR, Abdelhamed AM, Good CE, Mack AR, Bethel CR, Marshall S, Hujer AM, Hujer KM, Patel R, van Duin D, Fowler VG, Rhoads DD, Six DA, Moeck G, Uehara T, Papp-Wallace KM, and Bonomo RA
- Abstract
Taniborbactam, a bicyclic boronate β-lactamase inhibitor with activity against Klebsiella pneumoniae carbapenemase (KPC), Verona integron-encoded metallo-β-lactamase (VIM), New Delhi metallo-β-lactamase (NDM), extended-spectrum beta-lactamases (ESBLs), OXA-48, and AmpC β-lactamases, is under clinical development in combination with cefepime. Susceptibility of 200 previously characterized carbapenem-resistant K. pneumoniae and 197 multidrug-resistant (MDR) Pseudomonas aeruginosa to cefepime-taniborbactam and comparators was determined by broth microdilution. For K. pneumoniae (192 KPC; 7 OXA-48-related), MIC
90 values of β-lactam components for cefepime-taniborbactam, ceftazidime-avibactam, and meropenem-vaborbactam were 2, 2, and 1 mg/L, respectively. For cefepime-taniborbactam, 100% and 99.5% of isolates of K. pneumoniae were inhibited at ≤16 mg/L and ≤8 mg/L, respectively, while 98.0% and 95.5% of isolates were susceptible to ceftazidime-avibactam and meropenem-vaborbactam, respectively. For P. aeruginosa , MIC90 values of β-lactam components of cefepime-taniborbactam, ceftazidime-avibactam, ceftolozane-tazobactam, and meropenem-vaborbactam were 16, >8, >8, and >4 mg/L, respectively. Of 89 carbapenem-susceptible isolates, 100% were susceptible to ceftolozane-tazobactam, ceftazidime-avibactam, and cefepime-taniborbactam at ≤8 mg/L. Of 73 carbapenem-intermediate/resistant P. aeruginosa isolates without carbapenemases, 87.7% were susceptible to ceftolozane-tazobactam, 79.5% to ceftazidime-avibactam, and 95.9% and 83.6% to cefepime-taniborbactam at ≤16 mg/L and ≤8 mg/L, respectively. Cefepime-taniborbactam at ≤16 mg/L and ≤8 mg/L, respectively, was active against 73.3% and 46.7% of 15 VIM- and 60.0% and 35.0% of 20 KPC-producing P. aeruginosa isolates. Of all 108 carbapenem-intermediate/resistant P. aeruginosa isolates, cefepime-taniborbactam was active against 86.1% and 69.4% at ≤16 mg/L and ≤8 mg/L, respectively, compared to 59.3% for ceftolozane-tazobactam and 63.0% for ceftazidime-avibactam. Cefepime-taniborbactam had in vitro activity comparable to ceftazidime-avibactam and greater than meropenem-vaborbactam against carbapenem-resistant K. pneumoniae and carbapenem-intermediate/resistant MDR P. aeruginosa .- Published
- 2024
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17. Patient outcomes by baseline pathogen resistance phenotype and genotype in CERTAIN-1, a Phase 3 study of cefepime-taniborbactam versus meropenem in adults with complicated urinary tract infection.
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Moeck G, Gasink LB, Mendes RE, Woosley LN, Dorr M, Chen H, Wagenlehner FM, Henkel T, and McGovern PC
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- Humans, Adult, Female, Male, Pseudomonas aeruginosa drug effects, Pseudomonas aeruginosa genetics, Middle Aged, Double-Blind Method, Bacterial Proteins genetics, Genotype, Phenotype, Aged, Escherichia coli drug effects, Escherichia coli genetics, Treatment Outcome, Borinic Acids, Carboxylic Acids, Meropenem therapeutic use, Meropenem pharmacology, Cefepime therapeutic use, Cefepime pharmacology, Anti-Bacterial Agents therapeutic use, Anti-Bacterial Agents pharmacology, Urinary Tract Infections drug therapy, Urinary Tract Infections microbiology, Cephalosporins therapeutic use, Cephalosporins pharmacology, Microbial Sensitivity Tests, beta-Lactamases genetics
- Abstract
CERTAIN-1 was a Phase 3, double-blind, randomized, parallel group study of the efficacy and safety of cefepime-taniborbactam versus meropenem in the treatment of adults with complicated urinary tract infection (cUTI), including acute pyelonephritis. We determined susceptibility of Enterobacterales and Pseudomonas aeruginosa baseline pathogens to cefepime-taniborbactam and comparators and characterized β-lactam resistance mechanisms. Microbiologic response and clinical response were assessed in patient subsets defined by baseline pathogens that were of cefepime-, multidrug-, or carbapenem-resistant phenotype or that carried β-lactamase genes. Among Enterobacterales baseline pathogens, 26.8%, 4.1%, and 3.0% carried genes for extended-spectrum β-lactamases (ESBLs), AmpC, and carbapenemases, respectively. Within each treatment group, while composite success rates at Test of Cure in resistant subsets by pathogen species were similar to those by pathogen overall, composite success rates in meropenem patients were numerically lower for cefepime-resistant Escherichia coli (9/19; 47.4%) and ESBL E. coli (13/25; 52.0%) compared with E. coli overall (62/100; 62.0%). Cefepime-taniborbactam achieved composite success in 7/8 (87.5%) patients with carbapenem-resistant Enterobacterales and 8/9 (88.9%) patients with Enterobacterales with a carbapenemase gene (5 OXA-48-group; 2 KPC-3; 2 NDM-1). Cefepime-taniborbactam also achieved composite success in 8/16 (50.0%) patients and clinical success in 13/16 (81.3%) patients with P. aeruginosa ; corresponding rates were 4/7 (57.1%) and 6/7 (85.7%) for meropenem. Cefepime-taniborbactam demonstrated efficacy in adult cUTI patients with cefepime-, multidrug-, and carbapenem-resistant pathogens including pathogens with ESBL, AmpC, and carbapenemase genes., Clinical Trials: This study is registered with ClinicalTrials.gov as NCT03840148.
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- 2024
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18. Examining the activity of cefepime-taniborbactam against Burkholderia cepacia complex and Burkholderia gladioli isolated from cystic fibrosis patients in the United States.
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Mojica MF, Zeiser ET, Becka SA, LiPuma JJ, Six DA, Moeck G, and Papp-Wallace KM
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- Humans, United States, Cefepime pharmacology, Anti-Bacterial Agents pharmacology, beta-Lactamase Inhibitors pharmacology, beta-Lactamases, Microbial Sensitivity Tests, Burkholderia gladioli, Burkholderia cepacia complex, Cystic Fibrosis microbiology
- Abstract
The novel clinical-stage β-lactam-β-lactamase inhibitor combination, cefepime-taniborbactam, demonstrates promising activity toward many Gram-negative bacteria producing class A, B, C, and/or D β-lactamases. We tested this combination against a panel of 150 Burkholderia cepacia complex (Bcc) and Burkholderia gladioli strains. The addition of taniborbactam to cefepime shifted cefepime minimum inhibitory concentrations toward the provisionally susceptible range in 59% of the isolates tested. Therefore, cefepime-taniborbactam possessed similar activity as first-line agents, ceftazidime and trimethoprim-sulfamethoxazole, supporting further development., Competing Interests: D.A.S. and G.M. are employees of Venotorx Pharmaceuticals, Inc. Venatorx Pharmaceuticals, Inc., provided funding as a research grant to K.M.P-W. to conduct this study.
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- 2023
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19. In Vitro Activity of Cefepime-Taniborbactam and Comparators against Clinical Isolates of Gram-Negative Bacilli from 2018 to 2020: Results from the Global Evaluation of Antimicrobial Resistance via Surveillance (GEARS) Program.
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Karlowsky JA, Hackel MA, Wise MG, Six DA, Uehara T, Daigle DM, Cusick SM, Pevear DC, Moeck G, and Sahm DF
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- Cefepime pharmacology, Meropenem pharmacology, Tazobactam pharmacology, beta-Lactamases genetics, Pseudomonas aeruginosa, Gram-Negative Bacteria, Azabicyclo Compounds pharmacology, Microbial Sensitivity Tests, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Drug Resistance, Bacterial
- Abstract
Taniborbactam is a novel cyclic boronate β-lactamase inhibitor in clinical development in combination with cefepime. We assessed the in vitro activity of cefepime-taniborbactam and comparators against a 2018-2020 collection of Enterobacterales ( n = 13,731) and Pseudomonas aeruginosa ( n = 4,619) isolates cultured from infected patients attending hospitals in 56 countries. MICs were determined by CLSI broth microdilution. Taniborbactam was tested at a fixed concentration of 4 μg/mL. Isolates with cefepime-taniborbactam MICs of ≥16 μg/mL underwent whole-genome sequencing. β-lactamase genes were identified in meropenem-resistant isolates by PCR/Sanger sequencing. Against Enterobacterales , taniborbactam reduced the cefepime MIC
90 value by >64-fold (from >16 to 0.25 μg/mL). At ≤16 μg/mL, cefepime-taniborbactam inhibited 99.7% of all Enterobacterales isolates; >97% of isolates with multidrug-resistant (MDR) and ceftolozane-tazobactam-resistant phenotypes; ≥90% of isolates with meropenem-resistant, difficult-to-treat-resistant (DTR), meropenem-vaborbactam-resistant, and ceftazidime-avibactam-resistant phenotypes; 100% of VIM-positive, AmpC-positive, and KPC-positive isolates; 98.7% of extended-spectrum β-lactamase (ESBL)-positive; 98.8% of OXA-48-like-positive; and 84.6% of NDM-positive isolates. Against P. aeruginosa, taniborbactam reduced the cefepime MIC90 value by 4-fold (from 32 to 8 μg/mL). At ≤16 μg/mL, cefepime-taniborbactam inhibited 97.4% of all P. aeruginosa isolates; ≥85% of isolates with meropenem-resistant, MDR, and meropenem-vaborbactam-resistant phenotypes; >75% of isolates with DTR, ceftazidime-avibactam-resistant, and ceftolozane-tazobactam-resistant phenotypes; and 87.4% of VIM-positive isolates. Multiple potential mechanisms, including carriage of IMP, certain alterations in PBP3, permeability (porin) defects, and possibly, upregulation of efflux were present in most isolates with cefepime-taniborbactam MICs of ≥16 μg/mL. We conclude that cefepime-taniborbactam exhibited potent in vitro activity against Enterobacterales and P. aeruginosa and inhibited most carbapenem-resistant isolates, including those carrying serine carbapenemases or NDM/VIM metallo-β-lactamases (MBLs).- Published
- 2023
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20. Ceftibuten-Ledaborbactam Activity against Multidrug-Resistant and Extended-Spectrum-β-Lactamase-Positive Clinical Isolates of Enterobacterales from a 2018-2020 Global Surveillance Collection.
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Karlowsky JA, Wise MG, Hackel MA, Pevear DC, Moeck G, and Sahm DF
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- Ceftibuten therapeutic use, Microbial Sensitivity Tests, Serine, Azabicyclo Compounds pharmacology, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, beta-Lactamases genetics
- Abstract
Ceftibuten-ledaborbactam etzadroxil is a cephalosporin-boronate β-lactamase inhibitor prodrug combination under development as an oral treatment for complicated urinary tract infections caused by multidrug-resistant (MDR) Enterobacterales producing serine β-lactamases (Ambler class A, C, and D). In vivo , ledaborbactam etzadroxil (formerly VNRX-7145) is cleaved to the active inhibitor ledaborbactam (formerly VNRX-5236). To more completely define the breadth of ceftibuten-ledaborbactam's activity against important antimicrobial-resistant pathogens, we assessed its in vitro activity against phenotypic and genotypic subsets from a 2018-2020 global culture collection of 3,889 clinical isolates of Enterobacterales , including MDR organisms, extended-spectrum-β-lactamase (ESBL)-positive organisms, and organisms that are nonsusceptible and resistant to other antimicrobials. MICs were determined by CLSI broth microdilution and interpreted using both CLSI and EUCAST breakpoints. Ledaborbactam was tested at a fixed concentration of 4 μg/mL. β-Lactamase genes were characterized by PCR followed by Sanger sequencing or whole-genome sequencing for selected β-lactam-resistant isolate subsets. At ≤1 μg/mL, ceftibuten-ledaborbactam (MIC
90 , 0.25 μg/mL) inhibited 89.7% of MDR isolates, 98.3% of isolates with a presumptive ESBL-positive phenotype, and 92.6% of trimethoprim-sulfamethoxazole-nonsusceptible, 91.7% of levofloxacin-nonsusceptible, 88.1% of amoxicillin-clavulanate-nonsusceptible, 85.7% of ceftibuten-resistant (MIC >1 μg/mL), and 54.1% of carbapenem-nonsusceptible isolates. Against specific ESBL genotype-positive isolates (AmpC negative, serine carbapenemase negative, and metallo-β-lactamase negative), ceftibuten-ledaborbactam inhibited 96.3% of CTX-M-9 group (MIC90 , 0.25 μg/mL), 91.5% of CTX-M-1 group (MIC90 , 0.5 μg/mL), and 88.2% of SHV-positive (MIC90 , 2 μg/mL) isolates at ≤1 μg/mL. Against specific serine carbapenemase genotype-positive isolates, ceftibuten-ledaborbactam inhibited 85.9% of KPC-positive (MIC90 , 2 μg/mL) and 82.9% of OXA-48-group-positive (MIC90 , 2 μg/mL) isolates at ≤1 μg/mL. Continued development of ceftibuten-ledaborbactam appears warranted.- Published
- 2022
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21. Discovery of VNRX-7145 (VNRX-5236 Etzadroxil): An Orally Bioavailable β-Lactamase Inhibitor for Enterobacterales Expressing Ambler Class A, C, and D Enzymes.
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Trout RE, Zulli A, Mesaros E, Jackson RW, Boyd S, Liu B, Hamrick J, Daigle D, Chatwin CL, John K, McLaughlin L, Cusick SM, Weiss WJ, Pulse ME, Pevear DC, Moeck G, Xerri L, and Burns CJ
- Subjects
- Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents chemistry, Dose-Response Relationship, Drug, Enterobacteriaceae enzymology, Microbial Sensitivity Tests, Molecular Structure, Structure-Activity Relationship, beta-Lactamase Inhibitors chemical synthesis, beta-Lactamase Inhibitors chemistry, Anti-Bacterial Agents pharmacology, Drug Discovery, Enterobacteriaceae drug effects, beta-Lactamase Inhibitors pharmacology, beta-Lactamases metabolism
- Abstract
A major antimicrobial resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. The increasing emergence of β-lactamase-producing multi-drug-resistant "superbugs" has resulted in increases in costly hospital Emergency Department (ED) visits and hospitalizations due to the requirement for parenteral antibiotic therapy for infections caused by these difficult-to-treat bacteria. To address the lack of outpatient treatment, we initiated an iterative program combining medicinal chemistry, biochemical testing, microbiological profiling, and evaluation of oral pharmacokinetics. Lead optimization focusing on multiple smaller, more lipophilic active compounds, followed by an exploration of oral bioavailability of a variety of their respective prodrugs, provided 36 (VNRX-7145/VNRX-5236 etzadroxil), the prodrug of the boronic acid-containing β-lactamase inhibitor 5 (VNRX-5236). In vitro and in vivo studies demonstrated that 5 restored the activity of the oral cephalosporin antibiotic ceftibuten against Enterobacterales expressing Ambler class A extended-spectrum β-lactamases, class A carbapenemases, class C cephalosporinases, and class D oxacillinases.
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- 2021
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22. VNRX-5133 (Taniborbactam), a Broad-Spectrum Inhibitor of Serine- and Metallo-β-Lactamases, Restores Activity of Cefepime in Enterobacterales and Pseudomonas aeruginosa.
- Author
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Hamrick JC, Docquier JD, Uehara T, Myers CL, Six DA, Chatwin CL, John KJ, Vernacchio SF, Cusick SM, Trout REL, Pozzi C, De Luca F, Benvenuti M, Mangani S, Liu B, Jackson RW, Moeck G, Xerri L, Burns CJ, Pevear DC, and Daigle DM
- Subjects
- Bacterial Proteins chemistry, Bacterial Proteins genetics, Bacterial Proteins metabolism, Cefepime pharmacology, Microbial Sensitivity Tests, Protein Structure, Secondary, Pseudomonas aeruginosa drug effects, Anti-Bacterial Agents pharmacology, Borinic Acids pharmacology, Carboxylic Acids pharmacology, beta-Lactamase Inhibitors pharmacology
- Abstract
As shifts in the epidemiology of β-lactamase-mediated resistance continue, carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are the most urgent threats. Although approved β-lactam (BL)-β-lactamase inhibitor (BLI) combinations address widespread serine β-lactamases (SBLs), such as CTX-M-15, none provide broad coverage against either clinically important serine-β-lactamases (KPC, OXA-48) or clinically important metallo-β-lactamases (MBLs; e.g., NDM-1). VNRX-5133 (taniborbactam) is a new cyclic boronate BLI that is in clinical development combined with cefepime for the treatment of infections caused by β-lactamase-producing CRE and CRPA. Taniborbactam is the first BLI with direct inhibitory activity against Ambler class A, B, C, and D enzymes. From biochemical and structural analyses, taniborbactam exploits substrate mimicry while employing distinct mechanisms to inhibit both SBLs and MBLs. It is a reversible covalent inhibitor of SBLs with slow dissociation and a prolonged active-site residence time (half-life, 30 to 105 min), while in MBLs, it behaves as a competitive inhibitor, with inhibitor constant ( K
i ) values ranging from 0.019 to 0.081 μM. Inhibition is achieved by mimicking the transition state structure and exploiting interactions with highly conserved active-site residues. In microbiological testing, taniborbactam restored cefepime activity in 33/34 engineered Escherichia coli strains overproducing individual enzymes covering Ambler classes A, B, C, and D, providing up to a 1,024-fold shift in the MIC. Addition of taniborbactam restored the antibacterial activity of cefepime against all 102 Enterobacterales clinical isolates tested and 38/41 P. aeruginosa clinical isolates tested with MIC90 s of 1 and 4 μg/ml, respectively, representing ≥256- and ≥32-fold improvements, respectively, in antibacterial activity over that of cefepime alone. The data demonstrate the potent, broad-spectrum rescue of cefepime activity by taniborbactam against clinical isolates of CRE and CRPA., (Copyright © 2020 Hamrick et al.)- Published
- 2020
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23. Single Intravenous Dose of Oritavancin for Treatment of Acute Skin and Skin Structure Infections Caused by Gram-Positive Bacteria: Summary of Safety Analysis from the Phase 3 SOLO Studies.
- Author
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Corey GR, Loutit J, Moeck G, Wikler M, Dudley MN, and O'Riordan W
- Subjects
- Administration, Intravenous, Adult, Double-Blind Method, Female, Humans, Male, Middle Aged, Gram-Positive Bacteria drug effects, Gram-Positive Bacteria pathogenicity, Lipoglycopeptides administration & dosage, Lipoglycopeptides therapeutic use, Skin Diseases, Bacterial drug therapy
- Abstract
Oritavancin is a lipoglycopeptide with bactericidal activity against Gram-positive organisms. Its rapid concentration-dependent bactericidal activity and long elimination half-life allow single-dose treatment of acute bacterial skin and skin structure infections (ABSSSI). SOLO I and SOLO II were randomized, double-blind studies evaluating the efficacy and safety of a single 1,200-mg intravenous (i.v.) dose of oritavancin versus twice-daily i.v. vancomycin for 7 to 10 days in ABSSSI patients. Safety data from both studies were pooled for safety analysis. The database comprised pooled safety data for 976 oritavancin-treated patients and 983 vancomycin-treated patients. The incidences of adverse events, serious adverse events, and discontinuations due to adverse events were similar for oritavancin (55.3, 5.8, and 3.7%, respectively) and vancomycin (56.9, 5.9, and 4.2%, respectively). The median time to onset (3.8 days versus 3.1 days, respectively) and the duration (3.0 days for both groups) of adverse events were also similar between the two groups. The most frequently reported events were nausea, headache, and vomiting. Greater than 90% of all events were mild or moderate in severity. There were slightly more infections and infestations, abscesses or cellulitis, and hepatic and cardiac adverse events in the oritavancin group; however, more than 80% of these events were mild or moderate. Subgroup analyses did not identify clinically meaningful differences in the incidence of adverse events attributed to oritavancin. A single 1,200-mg dose of oritavancin was well tolerated and had a safety profile similar to that of twice-daily vancomycin. The long elimination half-life of oritavancin compared to that of vancomycin did not result in a clinically meaningful delay to the onset or prolongation of adverse events. (This study has been registered at ClinicalTrials.gov under registration no. NCT01252719 and NCT01252732.)., (Copyright © 2018 American Society for Microbiology.)
- Published
- 2018
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24. Evaluation of Oritavancin Dosing Strategies against Vancomycin-Resistant Enterococcus faecium Isolates with or without Reduced Susceptibility to Daptomycin in an In Vitro Pharmacokinetic/Pharmacodynamic Model.
- Author
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Belley A, Arhin FF, and Moeck G
- Subjects
- Daptomycin pharmacokinetics, Glycopeptides pharmacokinetics, Glycopeptides pharmacology, Gram-Positive Bacterial Infections drug therapy, Humans, Lipoglycopeptides pharmacokinetics, Microbial Sensitivity Tests methods, Vancomycin pharmacokinetics, Anti-Bacterial Agents pharmacology, Daptomycin pharmacology, Enterococcus faecium drug effects, Lipoglycopeptides pharmacology, Vancomycin pharmacology, Vancomycin Resistance drug effects, Vancomycin-Resistant Enterococci drug effects
- Abstract
The clinical development of nonsusceptibility to the lipopeptide antibiotic daptomycin remains a serious concern during therapy for infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The long-acting lipoglycopeptide oritavancin exhibits potent in vitro activity against VREfm, although its safety and efficacy for treating clinical VREfm infections have not been established. In this study, novel dosing regimens of daptomycin and oritavancin were assessed against both VREfm and daptomycin-nonsusceptible VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
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25. Comparative Pharmacodynamics of Single-Dose Oritavancin and Daily High-Dose Daptomycin Regimens against Vancomycin-Resistant Enterococcus faecium Isolates in an In Vitro Pharmacokinetic/Pharmacodynamic Model of Infection.
- Author
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Belley A, Lalonde-Séguin D, Arhin FF, and Moeck G
- Subjects
- Anti-Bacterial Agents pharmacokinetics, Daptomycin pharmacokinetics, Daptomycin pharmacology, Enterococcus faecium isolation & purification, Humans, Lipoglycopeptides, Microbial Sensitivity Tests, Vancomycin Resistance physiology, Vancomycin-Resistant Enterococci isolation & purification, Anti-Bacterial Agents pharmacology, Enterococcus faecium drug effects, Glycopeptides pharmacokinetics, Glycopeptides pharmacology, Gram-Positive Bacterial Infections drug therapy, Vancomycin-Resistant Enterococci drug effects
- Abstract
There are limited therapeutic options to treat infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The lipoglycopeptide oritavancin exhibits in vitro activity against this pathogen, although its utility against infections caused by VREfm has not been clinically established. In this study, the pharmacodynamic activity of free-drug levels associated with 12 mg/kg/day of daptomycin and a single 1,200-mg dose of oritavancin were determined against three VanA VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
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26. Effects of Oritavancin on Coagulation Tests in the Clinical Laboratory.
- Author
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Belley A, Robson R, Francis JL, Adcock DM, Tiefenbacher S, Rubino CM, Moeck G, Sylvester D, Dudley MN, and Loutit J
- Subjects
- Adult, Blood Coagulation Tests, Female, Hemostasis drug effects, Humans, Lipoglycopeptides, Male, Middle Aged, Young Adult, Anti-Bacterial Agents therapeutic use, Blood Coagulation drug effects, Glycopeptides therapeutic use
- Abstract
Previous studies have shown that some lipoglycopeptide and lipopeptide antimicrobial agents may cause falsely elevated values for some phospholipid-dependent coagulation tests. The effect of oritavancin, a lipoglycopeptide antibiotic, on coagulation test results was explored using pooled human plasma samples spiked with drug and in a clinical study after an infusion of a single 1,200-mg intravenous dose of oritavancin in normal healthy volunteers. Pooled plasma with oritavancin added ex vivo showed concentration-dependent prolongation of prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), and dilute Russell viper venom time (DRVVT) test results. In contrast, oritavancin had no effect on the activated protein C resistance assay, chromogenic anti-factor Xa assay (anti-FXa), thrombin time, and an immunoassay for the laboratory diagnosis of heparin-induced thrombocytopenia. In participants that received a single dose of oritavancin, elevations in PT/INR result, aPTT, DRVVT, activated clotting time, and silica clotting time occurred, with the maximum times to resolution of test interference determined to be 12, 120, 72, 24, and 18 h, respectively. The anti-FXa assay was unaffected, whereas transient elevations in D dimer levels were observed in 30% of participants, with a maximum time to resolution of 72 h. Although oritavancin has no impact on the coagulation system in vivo, a single dose of oritavancin can produce falsely elevated values of some coagulation tests used to monitor hemostasis. The interference of oritavancin on affected tests is transient, and the test results revert to normal ranges within specified times after dosing., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
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27. Comparative In Vitro Activities of Oritavancin, Dalbavancin, and Vancomycin against Methicillin-Resistant Staphylococcus aureus Isolates in a Nondividing State.
- Author
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Belley A, Lalonde Seguin D, Arhin F, and Moeck G
- Subjects
- Lipoglycopeptides, Microbial Sensitivity Tests, Teicoplanin pharmacology, Anti-Bacterial Agents pharmacology, Glycopeptides pharmacology, Methicillin-Resistant Staphylococcus aureus drug effects, Teicoplanin analogs & derivatives, Vancomycin pharmacology
- Abstract
Antibacterial agents that kill nondividing bacteria may be of utility in treating persistent infections. Oritavancin and dalbavancin are bactericidal lipoglycopeptides that are approved for acute bacterial skin and skin structure infections in adults caused by susceptible Gram-positive pathogens. Using time-kill methodology, we demonstrate that oritavancin exerts bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) isolates that are maintained in a nondividing state in vitro, whereas dalbavancin and the glycopeptide vancomycin do not., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
- Published
- 2016
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28. Results from Oritavancin Resistance Surveillance Programs (2011 to 2014): Clarification for Using Vancomycin as a Surrogate To Infer Oritavancin Susceptibility.
- Author
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Jones RN, Moeck G, Arhin FF, Dudley MN, Rhomberg PR, and Mendes RE
- Subjects
- Gram-Positive Bacteria drug effects, Lipoglycopeptides, Microbial Sensitivity Tests, Anti-Bacterial Agents pharmacology, Glycopeptides pharmacology, Vancomycin pharmacology
- Abstract
Measurement of vancomycin susceptibility has been shown to be highly predictive as a surrogate measure of oritavancin susceptibility among clinically indicated Gram-positive species. Results of studying over 30,000 pathogens (from 2011 to 2014) by cross-susceptibility analysis and determining the poor reproducibility of oritavancin-nonsusceptible results showed nearly perfect surrogate testing accuracy (99.86 to 99.94%). Any isolate of an indicated organism species with locally reproducible oritavancin-nonsusceptible results (extremely rare) should be referred to a reference laboratory for confirmation of the results and determination of the resistance mechanism., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
- Published
- 2016
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29. Use of in vitro vancomycin testing results to predict susceptibility to oritavancin, a new long-acting lipoglycopeptide.
- Author
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Jones RN, Turnidge JD, Moeck G, Arhin FF, and Mendes RE
- Subjects
- Enterococcus drug effects, Gram-Positive Bacteria drug effects, Lipoglycopeptides, Microbial Sensitivity Tests, Predictive Value of Tests, Reference Standards, Staphylococcus aureus drug effects, Streptococcus drug effects, Vancomycin Resistance drug effects, Anti-Bacterial Agents pharmacology, Drug Resistance, Bacterial drug effects, Glycopeptides pharmacology, Vancomycin pharmacology
- Abstract
Oritavancin is a recently approved lipoglycopeptide antimicrobial agent with activity against Gram-positive pathogens. Its extended serum elimination half-life and concentration-dependent killing enable single-dose treatment of acute bacterial skin and skin structure infections. At the time of regulatory approval, new agents, including oritavancin, are not offered in the most widely used susceptibility testing devices and therefore may require application of surrogate testing using a related antimicrobial to infer susceptibility. To evaluate vancomycin as a predictive susceptibility marker for oritavancin, 26,993 recent Gram-positive organisms from U.S. and European hospitals were tested using reference MIC methods. Organisms included Staphylococcus aureus, coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci (BHS), viridans group streptococci (VGS), and enterococci (ENT). These five major pathogen groups were analyzed by comparing results with FDA-approved susceptible breakpoints for both drugs, as well as those suggested by epidemiological cutoff values and supported by pharmacokinetic/pharmacodynamic analyses. Vancomycin susceptibility was highly accurate (98.1 to 100.0%) as a surrogate for oritavancin susceptibility among the indicated pathogen species. Furthermore, direct MIC comparisons showed high oritavancin potencies, with vancomycin/oritavancin MIC90 results of 1/0.06, 2/0.06, 0.5/0.12,1/0.06, and >16/0.06 μg/ml for S. aureus, CoNS, BHS, VGS, and ENT, respectively. In conclusion, vancomycin demonstrated acceptable accuracy as a surrogate marker for predicting oritavancin susceptibility when tested against the indicated pathogens. In contrast, 93.3% of vancomycin-nonsusceptible enterococci had oritavancin MIC values of ≤0.12 μg/ml, indicating a poor predictive value of vancomycin for oritavancin resistance against these organisms. Until commercial oritavancin susceptibility testing devices are readily available, isolates that when tested show vancomycin susceptibility can be inferred to be susceptible to oritavancin by using FDA-approved breakpoints., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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30. Pharmacodynamics of a simulated single 1,200-milligram dose of oritavancin in an in vitro pharmacokinetic/pharmacodynamic model of methicillin-resistant staphylococcus aureus infection.
- Author
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Belley A, Arhin FF, Sarmiento I, Deng H, Rose W, and Moeck G
- Subjects
- Analysis of Variance, Area Under Curve, Clinical Trials, Phase III as Topic, Colony Count, Microbial, Culture Media, Drug Dosage Calculations, Humans, Infusion Pumps, Lipoglycopeptides, Methicillin-Resistant Staphylococcus aureus growth & development, Microbial Sensitivity Tests, Staphylococcal Infections drug therapy, Staphylococcal Infections microbiology, Anti-Bacterial Agents pharmacology, Daptomycin pharmacology, Glycopeptides pharmacology, Methicillin-Resistant Staphylococcus aureus drug effects, Models, Biological, Vancomycin pharmacology
- Abstract
The safety and efficacy of a single 1,200-mg dose of the lipoglycopeptide oritavancin are currently being investigated in two global phase 3 studies of acute bacterial skin and skin structure infections. In this study, an in vitro pharmacokinetic/pharmacodynamic model was established to compare the free-drug pharmacodynamics associated with a single 1,200-mg dose of oritavancin to once-daily dosing with daptomycin at 6 mg/kg of body weight and twice-daily dosing with vancomycin at 1,000 mg against three methicillin-resistant Staphylococcus aureus (MRSA) strains over 72 h. The area under the bacterial-kill curve (AUBKC) was used to assess the antibacterial effect of each dosing regimen at 24 h (AUBKC(0-24)), 48 h (AUBKC(0-48)), and 72 h (AUBKC(0-72)). The rapid bactericidal activities of oritavancin and daptomycin contributed to lower AUBKC(0-24)s for the three MRSA strains than with vancomycin (P < 0.05, as determined by analysis of variance [ANOVA]). Oritavancin exposure also resulted in a lower AUBKC(0-48) and AUBKC(0-72) against one MRSA strain and a lower AUBKC(0-48) for another strain than did vancomycin exposure (P < 0.05). Furthermore, daptomycin exposure resulted in a lower AUBKC(0-48) and AUBKC(0-72) for one of the MRSA isolates than did vancomycin exposure (P < 0.05). Lower AUBKC(0-24)s for two of the MRSA strains (P < 0.05) were obtained with oritavancin exposure than with daptomycin. Thus, the antibacterial effect from the single-dose regimen of oritavancin is as effective as that from either once-daily dosing with daptomycin or twice-daily dosing with vancomycin against the MRSA isolates tested in an in vitro pharmacokinetic/pharmacodynamic model over 72 h. These results provide further justification to assess the single 1,200-mg dose of oritavancin for treatment of acute bacterial skin and skin structure infections.
- Published
- 2013
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31. Antimicrobial drug discovery through bacteriophage genomics.
- Author
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Liu J, Dehbi M, Moeck G, Arhin F, Bauda P, Bergeron D, Callejo M, Ferretti V, Ha N, Kwan T, McCarty J, Srikumar R, Williams D, Wu JJ, Gros P, Pelletier J, and DuBow M
- Subjects
- Anti-Bacterial Agents therapeutic use, Bacterial Infections drug therapy, Bacterial Infections metabolism, Bacterial Infections virology, Bacteriophages metabolism, Drug Design, Gene Expression Profiling methods, Genome, Viral, Humans, Staphylococcal Infections drug therapy, Staphylococcal Infections metabolism, Staphylococcal Infections virology, Bacterial Proteins metabolism, Drug Delivery Systems methods, Proteome metabolism, Staphylococcus Phages metabolism, Staphylococcus aureus metabolism, Staphylococcus aureus virology, Viral Proteins metabolism
- Abstract
Over evolutionary time bacteriophages have developed unique proteins that arrest critical cellular processes to commit bacterial host metabolism to phage reproduction. Here, we apply this concept of phage-mediated bacterial growth inhibition to antibiotic discovery. We sequenced 26 Staphylococcus aureus phages and identified 31 novel polypeptide families that inhibited growth upon expression in S. aureus. The cellular targets for some of these polypeptides were identified and several were shown to be essential components of the host DNA replication and transcription machineries. The interaction between a prototypic pair, ORF104 of phage 77 and DnaI, the putative helicase loader of S. aureus, was then used to screen for small molecule inhibitors. Several compounds were subsequently found to inhibit both bacterial growth and DNA synthesis. Our results suggest that mimicking the growth-inhibitory effect of phage polypeptides by a chemical compound, coupled with the plethora of phages on earth, will yield new antibiotics to combat infectious diseases.
- Published
- 2004
- Full Text
- View/download PDF
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