Antistaphylococcal Activity of CG400549, a New Experimental FabI Inhibitor, Compared with That of Other Agents

Bogdanovich, Tatiana; Clark, Catherine L.; Kosowska-Shick, Klaudia; Dewasse, Bonifacio; McGhee, Pamela; Appelbaum, Peter C.

doi:10.1128/aac.00550-07

Cited by 19 publications

(11 citation statements)

References 20 publications

(18 reference statements)

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“…During the course of the passage experiment, MIC values for XF-73 showed no more than a 4-fold increase from the starting MIC value, indicating that no resistance (defined as a Ͼ4-fold increase in MIC [4,7,21]) developed during the 55 passages (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…At passage number 55, with a daptomycin MIC of 32 g/ml (64-fold increase in original MIC), no further amino acid changes were observed in the targets sequenced in this investigation. a Resistance is defined as Ͼ4-fold increase in original MIC (4,7,21). b Passage number at which three successive elevated MICs were first obtained.…”

Section: Resultsmentioning

confidence: 99%

“…Vancomycin has been used as a comparator in a significant number of multipassage studies (3,4,6,7,20,21), and the emergence of resistance has been reported in only one of these (3). In our study, the initial MIC for vancomycin increased Ͼ4-fold in two of the four strains tested.…”

Section: Discussionmentioning

confidence: 99%

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Investigation of the Potential for Mutational Resistance to XF-73, Retapamulin, Mupirocin, Fusidic Acid, Daptomycin, and Vancomycin in Methicillin-Resistant Staphylococcus aureus Isolates during a 55-Passage Study

Farrell

Robbins

Rhys‐Williams³

et al. 2011

Antimicrob Agents Chemother

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XF-73 is a dicationic porphyrin drug with rapid Gram-positive antibacterial activity currently undergoing clinical trials for the nasal decolonization of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA). In multistep (55-passage) resistance selection studies in the presence of subinhibitory concentrations of XF-73, retapamulin, mupirocin, fusidic acid, and vancomycin against four Network on Antimicrobial Resistance in Staphylococcus aureus MRSA strains, there was no >4-fold increase in the MIC for XF-73 after 55 passages. In contrast, there was an increase in the MICs for retapamulin (from 0.25 g/ml to 4 to 8 g/ml), for mupirocin (from 0.12 g/ml to 16 to 512 g/ml), for fusidic acid (from 0.12 g/ml to 256 g/ml), and for vancomycin (from 1 g/ml to 8 g/ml in two of the four strains tested). Further investigations using S. aureus NRS384 (USA300) and daptomycin demonstrated a 64-fold increase in the MIC after 55 passages (from 0.5 g/ml to 32 g/ml) with a >4-fold increase in the MIC obtained after only five passages. Sequencing analysis of selected isolates confirmed previously reported point mutations associated with daptomycin resistance. No cross-resistance to XF-73 was observed with the daptomycin-resistant strains, suggesting that whereas the two drugs act on the bacterial cell membrane, their specific site of action differs. XF-73 thus represents the first in a new class of antibacterial drugs, which (unlike the comparator antibiotics) after 55 passages exhibited a <4-fold increase in MIC against the strains tested. Antibacterial drugs with a low propensity for inducing bacterial resistance are much needed for the prevention and treatment of multidrugresistant bacteria both within and outside the hospital setting.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Investigation of the Potential for Mutational Resistance to XF-73, Retapamulin, Mupirocin, Fusidic Acid, Daptomycin, and Vancomycin in Methicillin-Resistant Staphylococcus aureus Isolates during a 55-Passage Study

Farrell

Robbins

Rhys‐Williams³

et al. 2011

Antimicrob Agents Chemother

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“…Daily passages (minimum of 14) were performed until a significant increase in MIC (Ͼ4-fold) was obtained. Stability of the acquired resis- on May 9, 2018 by guest http://aac.asm.org/ tance was determined by MIC determinations after 10 daily passages of the variant on blood agar without antibiotics (3,4). A stable clone is defined as having an MIC after the drug-free passages within Ϯ1 of the MIC before the drug-free passages.…”

Section: ) Heterogeneous Vancomycin-intermediate S Aureus (Hvisa) mentioning

confidence: 99%

Resistance Selection Studies Comparing the Activity of Razupenem (PTZ601) to Vancomycin and Linezolid against Eight Methicillin-Resistant and Two Methicillin-Susceptible Staphylococcus aureus Strains

Clark

Kosowska-Shick

McGhee

et al. 2009

Antimicrob Agents Chemother

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Multistep and single-step resistance selection studies were performed with razupenem, linezolid, and vancomycin against 10 methicillin (meticillin)-resistant and -susceptible Staphylococcus aureus strains. After 20 daily subcultures, razupenem yielded only clones with MICs of >4 g/ml in one strain (8 g/ml) whose parent's MIC was already 4 g/ml. After 18 to 49 passages in 6/10 strains, razupenem MICs rose from 0.016 to 2 g/ml (parents) to 0.125 to 8 g/ml (with clones stable after 10 drug-free subcultures). Single-step mutant selection frequencies were similarly low for razupenem and comparators.

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“…Mutabilis [104], CrystalGenomics [105-107], and Affinium [17,20,21] are all focused on developing FabI inhibitors with Staphylococcus selective activity rather than broad-spectrum activity. These inhibitors are the first reported single-target, pathogen-selective inhibitors to enter into clinical evaluation.…”

Section: Antibiotic Discovery In Bacterial Fatty Acid Metabolismmentioning

confidence: 99%

Bacterial fatty acid metabolism in modern antibiotic discovery

Yao

Rock

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Bacterial fatty acid synthesis is essential for many pathogens and different from the mammalian counterpart. These features make bacterial fatty acid synthesis a desirable target for antibiotic discovery. The structural divergence of the conserved enzymes and the presence of different isozymes catalyzing the same reactions in the pathway make bacterial fatty acid synthesis a narrow spectrum target rather than the traditional broad spectrum target. Furthermore, bacterial fatty acid synthesis inhibitors are single-targeting, rather than multi-targeting like traditional monotherapeutic, broad-spectrum antibiotics. The single-targeting nature of bacterial fatty acid synthesis inhibitors makes overcoming fast-developing, target-based resistance a necessary consideration for antibiotic development. Target-based resistance can be overcome through multi-targeting inhibitors, a cocktail of single-targeting inhibitors, or by making the single targeting inhibitor sufficiently high affinity through a pathogen selective approach such that target-based mutants are still susceptible to therapeutic concentrations of drug. Many of the pathogens requiring new antibiotic treatment options encode for essential bacterial fatty acid synthesis enzymes. This review will evaluate the most promising targets in bacterial fatty acid metabolism for antibiotic therapeutics development and review the potential and challenges in advancing each of these targets to the clinic and circumventing target-based resistance.

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Antistaphylococcal Activity of CG400549, a New Experimental FabI Inhibitor, Compared with That of Other Agents

Cited by 19 publications

References 20 publications

Investigation of the Potential for Mutational Resistance to XF-73, Retapamulin, Mupirocin, Fusidic Acid, Daptomycin, and Vancomycin in Methicillin-Resistant Staphylococcus aureus Isolates during a 55-Passage Study

Investigation of the Potential for Mutational Resistance to XF-73, Retapamulin, Mupirocin, Fusidic Acid, Daptomycin, and Vancomycin in Methicillin-Resistant Staphylococcus aureus Isolates during a 55-Passage Study

Resistance Selection Studies Comparing the Activity of Razupenem (PTZ601) to Vancomycin and Linezolid against Eight Methicillin-Resistant and Two Methicillin-Susceptible Staphylococcus aureus Strains

Bacterial fatty acid metabolism in modern antibiotic discovery

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