MD Conference Express ICAAC 2011 - (Page 22)
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MA et al. Nature Rev Microbiol 2010]. Furthermore, bacteria that are deficient in ReA show increased susceptibility to fluouroquinolones, aminoglycosides, trimethoprim, some β-lactams, and other agents [Thi TD et al. J Antimicrob Chemother 2011; Lui et al. Antimicrob Agents Chemother 2010]. Lead candidate compound BRITE-345133, discovered by a collaborative effort between Dr. Singleton’s lab and Dr. Li-An Yeh’s lab at North Carolina Central University, is an allosteric inhibitor of RecA’s ATPase activity. BRITE-345133 has been shown to potentiate E. coli killing by ciprofloxacin (Figure 2), which translates into a dose-dependent reduction in ciprofloxacin MIC. An added benefit of RecA inhibition and improved bacterial killing is suppression of resistance emergence. New RecA inhibitors with improved physiochemical and activity spectra are under development. Figure 2. RecA Inhibitor BRITE-345133 Augments Bacterial Killing by Ciprofloxacin in vitro.
No Treatment Ciprofloxacin (0.5MIC) RecA inhibitor (only) Combination
inhibitor combinations, focusing on tazobactam, clavulanic, and a newer class of agents—avibactam (formerly called NXL-104) and MK-7655. Pipeline agents to watch include CXA-201, a 2-to-1 combination of a new cephalosporin (CXA-101) and tazobactam. CXA-201 demonstrates good activity against strains of P. aeruginosa with diverse resistance mechanisms [Cabot G et al. ICAAC 2010] but is less active against other gram-negative pathogens, particularly those that produce extended-spectrum β-lactamases (ESBLs) [Sader HS et al. Antimicrob Agents Chemother 2011]. A 4-to-1 combination of ceftazidime and avibactam is in development for use in complicated intraabdominal abscess (IAI) and urinary tract infections (UTIs) and is expected to enter Phase 3 by early 2012. This compound shows strong activity against E. coli, Klebsiella species, and Enterobacter species, including ESBL-producing strains [Sader HS et al. ICAAC 2010]. The addition of avibactam also improves ceftazidime’s activity against Pseudomonas strains with various resistance mechanisms [Eurofins Medinet Study #5006-08]. In a prospective trial for the treatment of UTI, similar efficacy was demonstrated for ceftazidime/avibactam compared with imipenem, and a greater proportion of ceftazidime-resistant E. coli responded favorably to ceftazidime/avibactam compared with imipenem (86% and 80%, respectively) [Vazquez JA et al. ECCMID 2011]. Other combinations of interest include a 1-to-1 combination of ceftaroline and avibactam that is in Phase 2 for complicated UTI and a triple combination of imipenem, cilastatin, and MK7655 that is in Phase 1. Dr. Shlaes concluded by emphasizing that he hopes drugmakers will heed the call to develop a compound, such as aztreonam (or other monobactam base agents) and avibactam (or MK7655), which should retain activity against gram-negative pathogens that bear NDM-1 or other metallo-β-lactamases. According to Joyce Sutcliffe, PhD, Tetraphase Pharmaceuticals, Watertown, Massachusetts, USA, Streptomyces that grew on stored grain supplied ancient cultures with naturally occurring tetracycline. The 1940s and 1950s saw the development of legacy and semisynthetic tetracyclines with great oral bioavailability, and now, a technique, called total synthesis, in which the right- and left-hand segments are designed in total and then connected together, has made possible the development of new classes of tetracyclines, including 8-aminomethyl, penta/polycyclic, and 7,9 disubstituted analogs. Dr. Sutcliffe presented information on several promising agents that are in development, including orally active compounds that are effective against multidrugresistant gram-positive and gram-negative pathogens.
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Reproduced with permission from J. Singleton, MD.
Terry Roemer, PhD, Merck Infectious Disease Research, Kenilworth, New Jersey, USA, presented his work on chemical genetic interaction networks that are aimed at uncovering targets for resensitization of methicillinresistant S. aureus (MRSA) to β-lactam antibiotics. Plasmid-based antisense interference is a technique that impairs transcription and translation of a targeted protein and has the potential to restore the susceptibility of MRSA to β-lactam antibiotics. A wide array of genes that are involved in β-lactam tolerance processes, including early- and late-stage peptidoglycan synthesis, cell division, and cell wall biogenesis, are potential antisense targets in MRSA [Lee et al. Chem Biol. In press 2011]. Dr. Roemer shared data regarding the development of small-molecule inhibitors to resistance targets that have been identified on genetic potentiation maps, including PC190723, a novel antistaphylococcal agent that targets a component of cell division initiation, FtsZ [Haydon DS et al. Science 2008]. David Shlaes, MD, Anti-Infectives Consulting, Stonington, Connecticut, USA, offered hope in the battle against microbial resistance in the form of new β-lactamase
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Table of Contents for the Digital Edition of MD Conference Express ICAAC 2011
MD Conference Express ICAAC 2011
Contents
Infectious Disease Genomics
Emerging Resistance Among Gram-Negative Pathogens
Procalcitonin-Guided Antibiotic Therapy In Patients with Lower Respiratory Tract Infections
Combination Therapy with Flucytosine Improves Survival in AIDS-Related Cryptococcal Meningitis
CXA-201 Effective Against Common ICU Pathogens
Tigecycline Plus Standard Therapy Is More Effective For Treating Infections in Febrile Neutropenic Cancer Patients
Interventions Aimed at Reducing MRSA BSIs Led to Decreased Rates of Nosocomial MSSA BSIs
Is the Effectiveness of aP Vaccine in Pre-Adolescents Insufficient?
TMC435 Effective in the Treatment of HCV Genotype 1 Infection
HIV
Vaccines
Antibiotic Resistance
Drug Discovery
The Conundrum of MDR TB and Combination Therapy
New Drugs to Treat MDR Pathogens
Immunizations in Reproductive Health
Why Can’t Microbes Just Get Along?
The Role of Adjunctive Steroids in the Treatment of Bacterial Meningitis
Human and Animal Viruses Share “One World” and Emerging Zoonotic Infections Continue to Threaten
MD Conference Express ICAAC 2011
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