XF-70 and XF-73, novel antibacterial agents active against slow-growing and non-dividing cultures of Staphylococcus aureus including biofilms

Ooi, Nicola; Miller, Keith; Randall, Chris; Rhys‐Williams, William; Love, William G.; Chopra, Ian

doi:10.1093/jac/dkp409

Cited by 84 publications

(71 citation statements)

References 18 publications

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“…Together with the lack of structure-specific resistance to the other drugs, these results suggest that the membranes of biofilm cells may be different from those of planktonic cells and that the structure (i.e., the matrix) of the biofilm acts as a shield for these more sensitive cells. This is in line with several recent studies that have shown that the cell membrane physiology changes significantly during biofilm growth (1,12,45,49,55). Thus, a picture is beginning to emerge wherein membrane charge and physiology are different in biofilm cells relative to their planktonic counterparts, and this difference can contribute to the efficacy of antibiotic therapy.…”

Section: Discussionsupporting

confidence: 85%

“…One approach to addressing these pharmacodynamics (PD) questions has been to compare the MICs of antibiotics for bacteria in biofilms (bMIC) to the corresponding MICs of those bacteria and drugs estimated by standard CLSI (13) liquid culture protocols (5,12,27,39,45,(49)(50)(51). A limitation of this method is an inability to control for the contribution of the physiological state and density of the bacteria in the biofilms in the way they are controlled for in the CLSI MIC protocol.…”

mentioning

confidence: 99%

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The Relative Contributions of Physical Structure and Cell Density to the Antibiotic Susceptibility of Bacteria in Biofilms

Kirby

Garner

Levin

2012

Antimicrob Agents Chemother

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For many bacterial infections, noninherited mechanisms of resistance are responsible for extending the term of treatment and in some cases precluding its success. Among the most important of these noninherited mechanisms of resistance is the ability of bacteria to form biofilms. There is compelling evidence that bacteria within biofilms are more refractory to antibiotics than are planktonic cells. Not so clear, however, is the extent to which this resistance can be attributed to the structure of biofilms rather than the physiology and density of bacteria within them. To explore the contribution of the structure of biofilms to resistance in a quantitative way, we developed an assay that compares the antibiotic sensitivity of bacteria in biofilms to cells mechanically released from these structures. Our method, which we apply to Escherichia coli and Staphylococcus aureus each with antibiotics of five classes, controls for the density and physiological state of the treated bacteria. For most of the antibiotics tested, the bacteria in biofilms were no more resistant than the corresponding populations of planktonic cells of similar density. Our results, however, suggest that killing by gentamicin, streptomycin, and colistin is profoundly inhibited by the structure of biofilms; these drugs are substantially more effective in killing bacteria released from biofilms than cells within these structures.

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Section: Discussionsupporting

confidence: 85%

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confidence: 99%

The Relative Contributions of Physical Structure and Cell Density to the Antibiotic Susceptibility of Bacteria in Biofilms

Kirby

Garner

Levin

2012

Antimicrob Agents Chemother

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“…As an example, the novel porphyrin antibacterial agents XF-70 and XF-73 were shown to remain highly active against this type of bacteria (Ooi et al, 2010). Hu et al (2010) found that the small quinolone-derived compound HT61 was active against non-multiplying MSSA and MRSA by causing depolarization of the cell membrane and destruction of the cell wall.…”

Section: Targeting the Persistent Microbial Phenotypementioning

confidence: 99%

Outcome and Prevention of Pseudomonas aeruginosa-Staphylococcus aureus Interactions During Pulmonary Infections in Cystic Fibrosis

Mitchell¹,

Malouin²

2012

Cystic Fibrosis - Renewed Hopes Through Research

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“…The presence of known resistance mechanisms was found not to have any effect on the antibacterial activity of XF-73 (10), suggesting that the mechanism of action of XF-73 is novel. XF-73 has also been shown to be equally active against nongrowing S. aureus and against S. aureus within biofilms (28). XF-73 is being developed as a topical drug to prevent and treat S. aureus, and MRSA infections and clinical trials are under way to assess the potential for the nasal decolonization of S. aureus.…”

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confidence: 99%

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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XF-70 and XF-73, novel antibacterial agents active against slow-growing and non-dividing cultures of Staphylococcus aureus including biofilms

Cited by 84 publications

References 18 publications

The Relative Contributions of Physical Structure and Cell Density to the Antibiotic Susceptibility of Bacteria in Biofilms

The Relative Contributions of Physical Structure and Cell Density to the Antibiotic Susceptibility of Bacteria in Biofilms

Outcome and Prevention of Pseudomonas aeruginosa-Staphylococcus aureus Interactions During Pulmonary Infections in Cystic Fibrosis

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

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