Bactericidal Activity of ACH-702 against Nondividing and Biofilm Staphylococci

Podos, Steven D.; Thanassi, Jane A.; Leggio, Melissa; Pucci, Michael J.

doi:10.1128/aac.00092-12

Cited by 18 publications

(14 citation statements)

References 42 publications

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“…7-Amino-substituted fluoroquinolone intermediates (3-7) were obtained by refluxing 1 in CH 3 CN, Et 3 N with piperidine, octahydro-1H-isoindole, perhydroisoquinoline, pyrrolidine, and morpholine in 48-89% yields [12]. Subsequently, intermediates 3-5 in DMF, DIPEA were coupled with thiazolidine in the presence of HATU at 70°C for 20-24 h to yield corresponding amides (8)(9)(10) in 54-60% yields [13] (Fig. 2).…”

Section: Chemistrymentioning

confidence: 99%

“…The corresponding acid chloride was treated with thiazolidine in the presence of Et 3 N to yield 42% of compound 2 [11]. Synthesis of 7-amino-substituted thiazolidine amide (8)(9)(10) and N-thiazolyl amide fluoroquinolone derivatives (11)(12)(13)(14) involved a two-step reaction sequence of nucleophilic aromatic substitution followed by acid derivatization to amides (Scheme 1). 7-Amino-substituted fluoroquinolone intermediates (3-7) were obtained by refluxing 1 in CH 3 CN, Et 3 N with piperidine, octahydro-1H-isoindole, perhydroisoquinoline, pyrrolidine, and morpholine in 48-89% yields [12].…”

Section: Chemistrymentioning

confidence: 99%

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Synthesis and Evaluation of Thiazolidine Amide and N‐Thiazolyl Amide Fluoroquinolone Derivatives

Garza

Wallace

Fernando

et al. 2017

Archiv der Pharmazie

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In an effort to develop new fluoroquinolones, we synthesized eight compounds and tested them against a panel of bacteria. The design of these compounds was guided by the introduction of the isothiazoloquinolone motif. The three most active compounds in this series, 8-10, demonstrated good antibacterial activity against methicillin-sensitive Staphylococcus aureus and healthcare-acquired methicillin-resistant Staphylococcus aureus (MIC 0.62-6.3 µg/mL). Further, when these three active compounds were tested for their inhibitory effects on bacterial enzymes, compound 9 was the most effective agent exhibiting IC values of 33.9 and 116.5 μM in the S. aureus deoxyribonucleic acid (DNA) gyrase supercoiling and topoisomerase IV decatenation assays, respectively.

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Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Synthesis and Evaluation of Thiazolidine Amide and N‐Thiazolyl Amide Fluoroquinolone Derivatives

Garza

Wallace

Fernando

et al. 2017

Archiv der Pharmazie

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“…Points above the line indicate that planktonic cells were less susceptible than biofilm cells. Sources: references 38, 64–66. doi:10.1128/microbiolspec.MB-0010-2014.f1210.1128/microbiolspec.MB-0010-2014.f12…”

Section: Figurementioning

confidence: 99%

Antimicrobial Tolerance in Biofilms

2015

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The tolerance of microorganisms in biofilms to antimicrobial agents is examined through a meta-analysis of literature data. A numerical tolerance factor comparing the rates of killing in the planktonic and biofilm states is defined to provide a quantitative basis for the analysis. Tolerance factors for biocides and antibiotics range over three orders of magnitude. This variation is not explained by taking into account the molecular weight of the agent, the chemistry of the agent, the substratum material, or the speciation of the microorganisms. Tolerance factors do depend on the areal cell density of the biofilm at the time of treatment and on the age of the biofilm as grown in a particular experimental system. This suggests that there is something that happens during biofilm maturation, either physical or physiological, that is essential for full biofilm tolerance. Experimental measurements of antimicrobial penetration times in biofilms range over orders of magnitude, with slower penetration (>12 min) observed for reactive oxidants and cationic molecules. These agents are retarded through the interaction of reaction, sorption, and diffusion. The specific physiological status of microbial cells in a biofilm contributes to antimicrobial tolerance. A conceptual framework for categorizing physiological cell states is discussed in the context of antimicrobial susceptibility. It is likely that biofilms harbor cells in multiple states simultaneously (e.g., growing, stress-adapted, dormant, inactive) and that this physiological heterogeneity is an important factor in the tolerance of the biofilm state.

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“…At concentrations reaching 16 times the MIC, this compound was able to reduce the activity of stationary phase biofilm associated cells of S. aureus by a factor of 3 log units 30 . ACH 702 is also active against a wide range of Gram-negative bacilli as well as Mycobacterium tuberculosis , which is particularly relevant in the era of drug resistant tuberculosis 31 , 32 …”

Section: How Would New Antibiotics Impact Favorably On Drug Resistance?mentioning

confidence: 99%

New antibiotic agents in the pipeline and how they can help overcome microbial resistance

2013

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Bacterial resistance is a growing threat and yet few new antibiotics active against multi-resistant bacteria are being explored. A combination of falling profits, regulatory mechanisms and irrational and injudicious use of antibiotics has led to an alarming situation where some infections have no cure. In this article, we summarize the new developments that have been suggested to incentivize the pharmaceutical industries toward the field of infections. We also briefly mention the new compounds on the horizon and some newly approved compounds that might help us tide over this crisis.

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Bactericidal Activity of ACH-702 against Nondividing and Biofilm Staphylococci

Cited by 18 publications

References 42 publications

Synthesis and Evaluation of Thiazolidine Amide and N‐Thiazolyl Amide Fluoroquinolone Derivatives

Synthesis and Evaluation of Thiazolidine Amide and N‐Thiazolyl Amide Fluoroquinolone Derivatives

Antimicrobial Tolerance in Biofilms

New antibiotic agents in the pipeline and how they can help overcome microbial resistance

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