XF-73, a novel antistaphylococcal membrane-active agent with rapid bactericidal activity

Ooi, Nicola; Miller, Keith; Hobbs, Joanne K.; Rhys‐Williams, William; Love, William G.; Chopra, Ian

doi:10.1093/jac/dkp299

Cited by 82 publications

(70 citation statements)

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“…In contrast, there was a significant increase in the MIC for three of the comparators against all the strains tested and two of four strains for vancomycin using the same conditions. XF-73 has a very rapid bactericidal activity (26,27) and acts on both dividing and nongrowing bacterial cells (28), and investigations suggest that it has a novel MOA (26,27). The results reported in this study confirm that such an antibacterial profile is likely to reduce the potential for the emergence of bacterial mutational resistance.…”

Section: Discussionsupporting

confidence: 68%

“…As the proposed antibacterial MOA for daptomycin (16,30) is similar to that proposed for XF-73 (26,27), both of which appear to target the bacterial membrane, resulting in membrane depolarization and loss of intracellular components, it was also included in this study. In vitro reduced susceptibility to daptomycin in S. aureus NRS384 (USA300) emerged after only five repeat passages and remained stable after 10 serial passages in drug-free conditions.…”

Section: Discussionmentioning

confidence: 99%

“…1), and previous studies have shown that XF-73 has potent Gram-positive in vitro bactericidal activity against a range of clinically important S. aureus isolates, including methicillin-sensitive S. aureus (MSSA), health care-associated MRSA (HA-MRSA), and CA-MRSA (minimal bactericidal concentration at which 90% of strains tested are killed [MBC 90 ], 0.5 g/ml) (10). XF-73 has rapid activity, with a Ͼ4-log reduction in CFU obtained after 5 min incubation in growth medium (27).…”

mentioning

confidence: 99%

“…Investigations into the mechanism of action of XF-73 against S. aureus demonstrated that the drug exhibits a rapid bacterial cell membrane-perturbing activity, which is likely to be responsible for the inhibition of macromolecular synthesis and the death of staphylococci exposed to the drug (26,27). 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.…”

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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: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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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“…These findings suggest that these novel compounds can be used as lead compounds for the development of antimicrobial agents. The potent inhibition of macromolecule synthesis and rapid bactericidal activity of compounds 1 and 3 suggested that they, like daptomycin 18 and XF-73, 19 might damage bacterial membranes. Further experiments are required to gain more insight into the exact mechanism of action of these novel compounds.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel deoxyribofuranosyl indole antimicrobial agents

et al. 2011

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Three novel deoxyribofuranosyl indole derivatives, FG050227 (1), FG050223 (2) and FG050204 (3), were identified as antimicrobial agents effective against Gram-positive bacterial strains and some fungi. The MIC values of (1), (2) and (3) against methicillin-resistant Staphylococcus aureus were 3.0, 6.0 and 13 lg ml À1 , respectively. Compounds 1 and 3 had bactericidal activity against exponentially growing S. aureus and inhibited biosynthesis of peptidoglycan, protein, RNA and DNA. Compound 2 was bacteriostatic and inhibited the biosynthesis of protein and RNA. The results indicated that deoxyribofuranosyl indole derivatives could be potential lead compounds for the development of antimicrobial agents. The Journal of Antibiotics (2012) 65, 53-57; doi:10.1038/ja.2011; published online 14 December 2011Keywords: bactericidal; macromolecule synthesis; MRSA; novel antimicrobial; VRE INTRODUCTIONThe emergence of resistant strains against antimicrobial agents is a serious problem in the clinical field. Staphylococcus aureus strains resistant to penicillin 1 and methicillin 2 were identified as early as 2 years after their initial use. Vancomycin-resistant enterococcus (VRE) emerged in 1987, 3 a few years after vancomycin began to be used worldwide. 4 S. aureus that is resistant to relatively intermediate concentrations of vancomycin was first reported in 1997 in Japan. 5 Linezolide and daptomycin, the antibiotics effective against methicillin-resistant Staphylococcus aures (MRSA) and VRE, became ineffective within 1 6 and 2 7,8 years after approval by Food and Drug Administration in the USA, respectively. Therefore, the discovery of novel antimicrobial agents effective against multi-drug resistant bacteria is crucial. Toward this aim, we screened chemical compounds against S. aureus. Here, we report the identification of three novel deoxyribofuranosyl indole compounds as potential antimicrobial agents against Gram-positive bacteria, including MRSA and VRE, and some fungi. MATERIALS AND METHODS Microbial strains and culture conditionsThe bacterial and fungal strains used in this study are summarized in Table 1. Bacterial cultures were prepared in either Luria Bertani (LB) medium (tryptone 10 g l À1 , yeast extract 5 g l À1 , NaCl 10 g l À1 ) or Muller-Hinton Broth (MHB) (DIFCO, Franklin Lakes, NJ, USA). For antimicrobial susceptibility tests, cation-adjusted MHB was used. Fungal suspensions were prepared in Roswell Park Memorial Institute medium (Sigma Aldrich, St Louis, MO, USA). Chemicals and antibioticsVancomycin, daptomycin and norfloxacin were purchased from Wako Pure Chemicals (Osaka, Japan), Sequoia Research Products (Pangbourne, UK), and Sigma Aldrich, respectively. Rifampicin and chloramphenicol were obtained from Nacalai Tesque (Kyoto, Japan). Radiolabelled Chemical library and screening methodOur chemical library contains intermediates of several natural product synthesis projects, (for example, K252a, 9 ecteinascidin 743, 10 kainic acid, 11 etc). The compounds were screened based on MIC values against meth...

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Mechanisms of Action of Microbicides

Lambert

2012

Russell, Hugo &Amp; Ayliffe's

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XF-73, a novel antistaphylococcal membrane-active agent with rapid bactericidal activity

Abstract: XF-73 exhibited rapid membrane-perturbing activity, which is likely to be responsible for inhibition of macromolecular synthesis and the death of staphylococci exposed to the drug.

Cited by 82 publications

References 10 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

Identification of novel deoxyribofuranosyl indole antimicrobial agents

Mechanisms of Action of Microbicides

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