Potent Sub-MIC Effect of GSK and Other Peptide Deformylase Inhibitors on the in vitro Growth of Staphylococcus aureus
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1 AAC Accepts, published online ahead of print on 28 October 2013 Antimicrob. Agents Chemother. doi: /aac Copyright 2013, American Society for Microbiology. All Rights Reserved. Potent Sub-MIC Effect of GSK and Other Peptide Deformylase Inhibitors on the in vitro Growth of Staphylococcus aureus Deborah Butler#, Dongzhao Chen 1, Karen O Dwyer, Thomas Lewandowski, Kelly Aubart and Magdalena Zalacain 2 Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, PA, USA Running Title: Potent sub-mic activity of GSK in S. aureus #corresponding author, address, Deborah.L.Butler@gsk.com Present address: 1 Wuxi Apptec, Philadelphia, PA, USA; 2 Zala Drug Discovery Consulting, West Chester, PA, USA
2 ABSTRACT Peptide deformylase (PDF), a clinically unexploited antibacterial target, plays an essential role in protein maturation. PDF inhibitors, therefore, represent a new antibiotic class with a unique mode of action that provides an alternative therapy for the treatment of infections caused by drug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). GSK is a novel PDF inhibitor in Phase II clinical development for the treatment of lower respiratory tract and skin infections. We have discovered that PDF inhibitors can prevent S. aureus in vitro growth for up to 6 hours at concentrations 8- to 32-fold below their MIC. This phenomenon seems specific to PDF inhibitors, as none of the antimicrobial agents with alternative mechanisms of action tested show such a potent and widespread effect. It also appears limited to S. aureus, as PDF inhibitors do not show such an inhibition of growth at sub-mic concentrations in Streptococcus pneumoniae or Haemophilus influenzae. Analysis of the effect of GSK on the early growth of 100 randomly selected S. aureus strains shows that concentrations equal to or below 1/8 MIC inhibit growth of 91% of the strains tested for 6 hours, while the corresponding amount of moxifloxacin or linezolid only affects the growth of 1% and 6% of strains, respectively. Furthermore, the sub-mic effect demonstrated by GSK appears more substantial on those strains at the higher end of the MIC spectrum. These effects may impact the clinical efficacy of GSK in serious infections caused by multidrug-resistant S. aureus.
3 INTRODUCTION Resistance to marketed antibiotics has been a global health concern for a number of years, particularly with the appearance of strains resistant to multiple antimicrobial agents. Staphylococcus aureus accounts for 16% of the most common hospital-acquired infections (HAIs), the highest number associated with a single pathogen (1), with methicillin-resistant S. aureus (MRSA) being responsible for more than 50% of them (1). Although there have been encouraging reports that show a decrease in the number of invasive healthcare-associated MRSA infections (HA-MRSA) (1, 2), a continuous increase in the number of invasive community-associated MRSA (CA-MRSA) infections has been observed in the last decade (3). PDF is a highly conserved metalloprotease that catalyzes the removal of the N- terminal formyl group from all nascent polypeptides (4-6), a function essential for bacterial growth (7-10) and, therefore, an attractive target for the development of new broad-spectrum antibacterial agents. The considerable effort invested over the past decade in the discovery of PDF inhibitors for clinical use has yielded a significant number of chemically diverse molecules with antibacterial activity and efficacy in animal models of infection (11-13). One compound, GSK (14), has shown good safety and pharmacokinetic properties (15-18) and is currently in Phase II development. In this study, we report that GSK and other PDF inhibitors can prevent S. aureus in vitro growth for 6 hours at concentrations 8- to 32-fold below their MIC. This effect seems specific to S. aureus and PDF inhibitors, and is not consistently observed with other antibiotics tested inhibiting alternative bacterial targets, or with PDF inhibitors against other organisms.
4 MATERIALS AND METHODS Bacterial Strains and Growth Conditions. One hundred S. aureus clinical isolates (75 MRSA and 25 MSSA, International Health Management Associates, Schaumburg, IL), randomly selected from a larger GSK in vitro surveillance study (14), were used in this analysis. Additional S. aureus (124429, PK2, Newman, and X32601), S. pneumoniae (1629, Ery-2, S, and ATCC6303) and H. influenzae (511343, H, L317/3, and H128) strains used were obtained from the GlaxoSmithKline Anti-Infectives Culture Collection. S. pneumoniae and S. aureus strains were cultured at 35 o C on Trypticase Soy Agar (TSA) with 5% sheep blood or in Cation-Adjusted Mueller Hinton broth. H. influenzae strains were cultured at 35 o C on Chocolate Agar II plates or in Haemophilus Test Medium broth. Antimicrobial Agents and Susceptibility Testing. PDF inhibitors GSK and GSK (19) were obtained from GlaxoSmithKline Pharmaceuticals (Collegeville, PA). Other antibacterial agents used in this analysis were provided by their manufacturers in the USA or by Sigma (Sigma Pharmaceuticals, Monticello, IA). Minimum inhibitory concentrations (MIC) were determined by broth microdilution according to Clinical and Laboratory Standards Institute guidelines (20). Bacterial Count Viability Assay. In order to determine the number of viable bacterial cells, samples were removed at regular time intervals from the different wells of standard MIC plate assays where every time point was an independent MIC study. Viable bacterial counts were performed at assay set-up (time 0) and every two hours up
5 to 20 hours incubation, by plating three 20 µl aliquots from each MIC assay well onto the appropriate agar plates. Plates were incubated overnight at 35 C and colony counts were determined at the dilution that provided distinguishable colonies (10-50 colonies depending on bacterial species). An average of the three counts was used to estimate the number of colony forming units (CFU) per ml in the original sample. BacTitre-Glo Viability Assay. The BacTitre-Glo Microbial Cell Viability Assay (Promega, Madison, WI) determines the number of viable bacterial cells in a liquid sample through quantification of ATP production by addition of a thermostable luciferase and measurement of a luminescent signal. This assay is amenable to high throughput and provides a more direct and immediate measurement of bacterial viability (21). Samples (50 µl) were taken from each compound concentration in a standard MIC plate after 6 hours incubation and ATP production was measured as relative light units (RLU) according to the manufacturer s recommendations using an Infinite microplate reader (Tecan US, Morrisville, NC). Percent inhibition of growth was calculated as: [1 (RLU sample background / RLU control background)] X100 where RLU sample were the RLU in each compound-containing well, RLU control were the RLU in the no-compound well and the RLU at the 4X MIC well was used as background. This assay was carried out in duplicate using two inoculum preparations in separate assay plates in order to assess reproducibility and to increase confidence in the data. Good reproducibility of ATP quantification between the duplicate trials was
6 observed with the concentration of compound that reduced growth by 95% being the same or within two-fold in most cases. When the results varied two-fold, the percent inhibition was calculated from the average of both ATP quantifications. In those cases where the results differed by four-fold, the assay was repeated in duplicate. A linear correlation was observed between luminescent signal and the amount of cells present in cultures of S. aureus strains, PK2, , Newman, and X32601, with coefficients of determination (R2 values) for the two sets of data of 0.89, 0.93, 0.99, and 0.99, respectively. Mice. Male CD-1 mice (20-25 g) (Charles River Laboratories, Wilmington, MA), used in the experimental models, were allowed food and water ad libitum. All procedures were performed in accordance with protocols approved by the GlaxoSmithKline Institutional Animal Care and Use Committee, and met or exceeded the standards of the American Association for the Accreditation of Laboratory Animal Care, the United States Department of Health and Human Services, and all local and federal animal welfare laws. Murine groin infection model. S. aureus cultures, grown overnight in Brain Heart Infusion broth, were diluted 1:20 into phosphate-buffered saline (PBS). Bacterial suspensions were further diluted 1:10 into 0.6% (w/v) semi-solid nutrient agar. Six mice/group were inoculated with 0.5 ml of this suspension (containing approximately 2x10 6 CFU/mouse) by subcutaneous injection in the femoral region. Starting 1 hr after infection, mice were dosed with GSK twice daily for 4 days. The mice were
7 euthanized 96 hr after infection, the abscess removed, placed into a stomacher bag with 1 ml of PBS and homogenized for 2 min in a Stomacher 80 biomaster (Seward). Ten fold serial dilutions in sterile saline were plated on TSA supplemented with 5% sheep blood for enumeration of viable bacteria. Quantification of GSK in blood samples. Approximately 30 ml of whole blood was serially collected from the lateral tail vein of mice at 0.083, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post-dose into heparin-coated capillary tubes (Drummond Scientific, Broomall, PA). Blood (10 ml) was transferred into a microfuge tube and mixed with 10 ml cold HPLC-grade water. All samples were frozen immediately on dry ice and maintained at -80 C until analyzed by LC/MS/MS with the appropriate concentration curve.
8 RESULTS Efficacy of GSK against S. aureus strains in a murine groin abscess infection model is, in some cases, better than expected. A substantial number of PDF inhibitors demonstrated good in vivo activity in murine S. aureus groin abscess infection models in spite of having free fraction blood levels that did not always reach their MIC. Therefore, a study was designed to evaluate the oral efficacy of GSK against three S. aureus strains with MICs of 0.5, 2 and 8 g/ml. As depicted in Figure 1 (A and B), the efficacy of GSK administered orally at 150 mg/kg was similar among all strains, despite the fact that free blood levels peaked at 1.05 g/ml, and never achieved the MIC of the compound against two of the three strains. PDF inhibitors prevent initial S. aureus growth at concentrations as low as 16-fold below their MIC. In order to improve our understanding of the inhibitory effect of PDF inhibitors on S. aureus growth, a study was carried out to determine the number of viable bacterial cells in the wells of a standard MIC plate with GSK and S. aureus (MIC of 4 µg/ml). The study was completed as two separate experiments with samples taken at time points 0 10 hours on day 1 and at time points hours on day 2 (Figure 2A). Concentrations of GSK as low as 0.25 µg/ml (1/16 MIC) prevented growth of this S. aureus strain during the first 6 hours and 0.5 µg/ml (1/8 MIC) could prevent growth for 8 hours (Figure 2A). However, as expected, after the standard hours incubation, the GSK MIC for this organism was 4 µg/ml. An identical MIC pattern was observed when the bacterial inoculum was obtained from wells treated with sub-mic concentrations of GSK466222,
9 indicating that the growth observed at 20 hours is not the consequence of resistance development. Similar to the results obtained with S. aureus , both GSK and an additional PDF inhibitor, GSK , demonstrated a strong inhibition of S. aureus PK2 growth for 6 hours at 1/16 MIC (Figure 2B). On the other hand, sub-mic concentrations of moxifloxacin and linezolid did not significantly inhibit growth of S. aureus PK2 after the first 2 hours. Rapid killing could be seen with moxifloxacin at MIC concentrations up to 8 hours incubation, but there was growth at 1/4 MIC and 1/8 MIC after 2 hours incubation (Table 2B). Linezolid showed inhibition of growth at concentrations corresponding to 1/4 MIC for the first 6-8 hours incubation but at concentrations of 1/8 and 1/16 MIC there was significant growth after 2 hours (Figure 2B). In order to further investigate the extent of these findings and to determine if the phenomenon was limited to S. aureus, BacTitre-Glo was used to assess the effect of a larger number of compounds against a broader diversity of organisms after 6 hours incubation. A second methodology confirms a potent inhibitory effect of PDF inhibitors on initial S. aureus growth at sub-mic concentrations. Cell growth was evaluated, via ATP production, in four S. aureus cultures (PK2, , Newman, and X32601) in the presence of various multiples and fractions of MIC of three PDF inhibitors and other standard antibacterial agents (Table 1). A potent growth inhibitory effect was consistently observed in these four S. aureus strains at concentrations between 1/8 and
10 1/32 of their MIC only with PDF inhibitors, although mupirocin and tetracycline prevented growth of S. aureus Newman at concentrations of 1/8 and 1/32 MIC, respectively. To clarify whether this effect was unique to S. aureus, growth inhibition studies were performed with four strains each of S. pneumoniae and H. influenzae in the presence of variable amounts of GSK or moxifloxacin (Table 1). For both organisms, concentrations of GSK near the MIC were necessary to inhibit 95% of bacterial growth (Table 1). Sub-MIC concentrations of GSK inhibit growth of 91% of S. aureus strains for 6 hours. In order to ascertain the breadth of this finding, inhibition of growth of 100 randomly selected S. aureus strains was assessed after 6 hours incubation at various multiples and fractions of the MIC of GSK , moxifloxacin and linezolid. MICs for these strains ranged from 0.5 to 4 g/ml for GSK , 1 to 4 g/ml for linezolid and 0.03 to 16 g/ml for moxifloxacin. Only 99 strains were tested with moxifloxacin, as one was highly resistant to this antibiotic (MIC, >32 g/ml). Moxifloxacin showed no significant growth inhibition at sub-mic concentrations in 98 of the 99 strains tested after 6 hours incubation (Figure 3). Growth inhibition 95% was achieved at moxifloxacin concentrations of 1/8 MIC only in one case, whereas four strains needed 1/2 MIC and the additional 94 strains required MIC concentrations or greater.
11 With linezolid, 90 of the 100 strains tested had 95% growth inhibited at concentrations 4-fold below the MIC and 4/100 strains required 1/2 MIC concentrations. This compound had an initial potent sub-mic effect in 6 of the 100 strains with substantial growth inhibition at 1/8 MIC (Figure 3). In contrast, GSK demonstrated a strong sub-mic inhibitory effect with 95% growth of 91 of the 100 strains inhibited at concentrations of 1/8 MIC or lower (Figure 3). In fact, concentrations 1/16 MIC or below inhibited growth of 62% of the strains after 6 hours incubation and one isolate showed 95% growth inhibition at 1/128 MIC. Of the remaining 9 isolates, 8 required concentrations of 1/4 MIC and one required 1/2 MIC to prevent 95% growth. Relationship between GSK MIC and fraction of MIC necessary to inhibit >95% of S. aureus growth. A detailed analysis of the data demonstrated that the initial growth of strains with the highest GSK MICs could be prevented with smaller MIC fractions (Figure 4). In fact, concentrations equal or below 1/16 MIC inhibited early growth of 41% (7/17), 69% (49/71) and 83% (5/6) of the strains with MIC values of 1, 2 and 4 g/ml, respectively. Although few strains with MICs at both ends of the spectrum (0.5 and 4 g/ml) were included in this study, concentrations equal or lower than 1/8 GSK MIC did not show an inhibitory effect against most of the isolates with the lowest MIC whereas they did against 97% (69/71) and 100% (6/6) of the strains with MICs of 2 and 4 g/ml, respectively (Figure 4).
12 DISCUSSION S. aureus is a commensal organism with a versatile arsenal of virulence factors that enable it to invade and colonize all types of tissues and to evade host defenses (22). This bacterium is the causative agent of a number of common infections in skin, soft tissue, respiratory system, joints and bones and is responsible for life-threatening clinical conditions such as pneumonia, bacteremia, endocarditis, and toxic shock syndrome (22). PDF is one of only a few clinically unexploited targets with an antimicrobial candidate in development. This enzyme is ubiquitous in bacteria, where it plays an essential role in protein maturation, and is not necessary for eukaryotic cytoplasmic protein synthesis, which starts with unformylated methionine. Inhibitors of PDF have demonstrated activity against S. aureus in vitro (12, 23-26), in animal models of infection (27), and in a Phase IIa study (O. Naderer, submitted for publication). Unexpected results showing better than anticipated efficacy of PDF inhibitors in murine S. aureus groin abscess infection models prompted an investigation into the effect of these compounds on the in vitro growth of S. aureus. Initial experiments showed a pronounced inhibitory effect of PDF inhibitors GSK and GSK on the first 6-8 hours of S. aureus growth at concentrations 8 to 16-fold below the MIC, which was not observed with the bactericidal DNA gyrase inhibitor moxifloxacin or the bacteriostatic protein synthesis inhibitor linezolid. More extensive studies investigating the effect of three PDF inhibitors and 10 comparator agents with different modes of antibacterial action on S. aureus growth corroborated these results. All the PDF inhibitors could prevent 95% of the growth of four S. aureus strains for 6 hours at concentrations ranging between 1/8 and 1/32 of their respective MICs. None of the other
13 antimicrobial agents showed such a potent and widespread sub-mic effect, although linezolid demonstrated a consistent growth inhibition of all strains at 1/4 MIC concentrations. This property of PDF inhibitors may be limited primarily to S. aureus, as sub-mic concentrations did not have such a profound effect on the growth of S. pneumoniae or H. influenzae strains. A study comparing the effect of GSK , linezolid and moxifloxacin on the first 6 hours of growth of 100 randomly selected S. aureus strains showed that concentrations 8-fold below the GSK MIC inhibited 95% growth of 91% of the strains while the corresponding amount of moxifloxacin or linezolid could only prevent growth of 1% and 6% of the strains, respectively. Analysis of the relationship between GSK MIC and the fraction of MIC necessary to inhibit 95% of the early S. aureus growth revealed an interesting trend that, if confirmed, could have clinical implications for this compound. Concentrations of GSK equal to or below 1/8 MIC had a potent inhibitory effect on the early growth of only 25% (1/4) of S. aureus strains with MICs of 0.5 g/ml, but affected 82.4% (14/17) of those with MICs of 1 g/ml and 97.4% (69/71) and 100% (6/6) of the strains with GSK MIC of 2 and 4 g/ml, respectively. Therefore, although additional studies with larger numbers of strains at the extreme ends of the MIC distribution would be revealing, it seems that GSK has a stronger sub-mic effect on strains with higher MICs. This observation could explain the results obtained in the efficacy studies with GSK466222, as the initial in vitro growth of the two S. aureus strains with higher MIC, PK2 and X32601, is inhibited at concentrations 1/16 and 1/8 MIC, respectively, whereas concentrations of 1/2 MIC were necessary to inhibit growth of S. aureus (data not shown).
14 Therefore, the amount of GSK necessary to inhibit the first 6 hours of growth of all three strains would be very similar, and, as the compound is dosed twice a day for four days, this effect would be exerted at regular intervals. In addition, recent PK/PD analysis of GSK in eight S. aureus strains with MICs ranging from 0.5 to 4 g/ml demonstrates a lack of correlation between the MIC and the free AUC necessary for efficacy. Instead, efficacious AUCs were similar against all strains, independent of their MIC (T. Lewandowski, J.L. Hoover and S. Rittenhouse, presented at the 23 rd European Congress of Clinical Microbiology and Infectious Diseases, Berlin, Germany, 27 to 30 April 2013). Although an extensive bioinformatic analysis comparing the genomes of strains inhibited and not inhibited by sub-mic concentrations of PDF inhibitors was conducted, no differences were identified that could explain this phenomenon. While no changes were observed between the promoter/coding regions of the pdf genes from strains showing a potent sub-mic effect and those that did not, a thorough transcription analysis of this gene might provide some insight on the possible induction of PDF expression by PDF inhibitors in some S. aureus strains. Whereas the in vitro activity of an antibiotic can be readily determined by simple methodologies, its efficacy in vivo is the result of the complex interrelation of a number of parameters that can be, at best, only measured individually. Consequently, pharmacokinetic/pharmacodynamic (PK/PD) studies are a critical step in the process of predicting the antibiotic doses necessary for clinical efficacy. Although PK/PD parameters have been shown to be good predictors of efficacy, they are always reported in relation to the in vitro MIC. Not taken into account is any effect that the antibiotic
15 may have at subinhibitory concentrations, a situation frequently encountered during the normal course of antibiotic therapy. Specifically in S. aureus, it has already been reported that subinhibitory concentrations of certain antibiotics can inhibit exoprotein production (28) including critical virulence factors such as -toxin (29, 30), increase susceptibility to phagocytosis (29), and modulate adherence to fibronectin (31, 32) and even biofilm formation (33, 34). These effects may be important in the successful treatment of S. aureus infections and should perhaps be taken into consideration in the selection of therapy (30). In conclusion, we report that sub-mic concentrations of PDF inhibitors prevent the first 6 hours of S. aureus in vitro growth. In addition, our results indicate that this growth inhibition is more pronounced for strains at the higher end of the MIC distribution and, consequently, there may not be a linear relationship, within the wild-type frequency distribution, between the concentration of compound necessary for efficacy and the MIC of the strain causing the infection. Additional studies will be necessary to elucidate the mechanism behind this unusual observation and to understand any potential implications for the clinical efficacy of GSK and other PDF inhibitors against S. aureus infections.
16 REFERENCES 1. Sievert DM, Ricks P, Edwards JR, Schneider A, Patel J, Srinivasan A, Kallen A, Limbago B, Fridkin S Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, Infect. Control Hosp. Epidemiol. 34: Kallen AJ, Mu Y, Bulens S, Reingold A, Petit S, Gershman K, Ray SM, Harrison LH, Lynfield R, Dumyati G, Townes JM, Schaffner W, Patel PR, Fridkin SK Health care-associated invasive MRSA infections, JAMA 304: David MZ, Daum RS Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin. Microbiol. Rev. 23: Adams JM On the release of the formyl group from nascent protein. J. Mol. Biol. 33: Ball LA, Kaesberg P Cleavage of the N-terminal formylmethionine residue from a bacteriophage coat protein in vitro. J. Mol. Biol. 79: Livingston DM, Leder P Deformylation and protein biosynthesis. Biochemistry 8: Mazel D, Pochet S, Marliere P Genetic characterization of polypeptide deformylase, a distinctive enzyme of eubacterial translation. EMBO J. 13:
17 8. Meinnel T, Blanquet S Characterization of the Thermus thermophilus locus encoding peptide deformylase and methionyl-trna(fmet) formyltransferase. J. Bacteriol. 176: Margolis PS, Hackbarth CJ, Young DC, Wang W, Chen D, Yuan Z, White R, Trias J Peptide deformylase in Staphylococcus aureus: resistance to inhibition is mediated by mutations in the formyltransferase gene. Antimicrob. Agents Chemother. 44: Margolis P, Hackbarth C, Lopez S, Maniar M, Wang W, Yuan Z, White R, Trias J Resistance of Streptococcus pneumoniae to deformylase inhibitors is due to mutations in defb. Antimicrob. Agents Chemother. 45: Aubart K, Zalacain M Peptide deformylase inhibitors. Prog. Med. Chem. 44: Lofland D, Difuntorum S, Waller A, Clements JM, Weaver MK, Karlowsky JA, Johnson K In vitro antibacterial activity of the peptide deformylase inhibitor BB J. Antimicrob. Chemother. 53: Fritsche TR, Sader HS, Cleeland R, Jones RN Comparative antimicrobial characterization of LBM415 (NVP PDF-713), a new peptide deformylase inhibitor of clinical importance. Antimicrob. Agents Chemother. 49: O'Dwyer K, Hackel M, Hightower S, Hoban D, Bouchillon S, Qin D, Aubart K, Zalacain M, Butler D Comparative analysis of the antibacterial activity of a novel peptide deformylase inhibitor, GSK Antimicrob. Agents Chemother. 57:
18 15. Naderer OJ, Dumont E, Zhu J, Kurtinecz M, Jones LS Safety, tolerability and pharmacokinetics of repeat dosing of the antibiotic GSK , a peptide deformylase inhibitor: a randomized placebo-controlled study. J. Antimicrob. Chemother. 68: Naderer OJ, Dumont E, Zhu J, Kurtinecz M, Jones LS Single-dose safety, tolerability, and pharmacokinetics of the antibiotic GSK , a novel peptide deformylase inhibitor. Antimicrob. Agents Chemother. 57: Naderer OJ, Dumont E, Zhu J, Kurtinecz M, Jones LS Effect of H2 blockade and food on single-dose pharmacokinetics of GSK , a peptide deformylase inhibitor antibacterial. Antimicrob. Agents Chemother. 57: Naderer OJ, Jones LS, Zhu J, Kurtinecz M, Dumont E Safety, tolerability, and pharmacokinetics of oral and intravenous administration of GSK , a peptide deformylase inhibitor. J. Clin. Pharmacol. Article published online: 13 AUG 2013, DOI: /jcph Qin D, Norton B, Liao X, Knox AN, Fang Y, Lee J, Dreabit JC, Christensen SB, Benowitz AB, Aubart KM [(Pyrimidinylhydrazino)-3- oxopropyl]hydroxyformamide derivatives as bacterial peptide deformylase inhibitors and preparation, pharmaceutical compositions and use in the treatment of bacterial infections. PCT Int. Appl.WO A1. (Example 25). 20. Clinical and Laboratory Standards Institute Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 8th ed.
19 Approved standard M07-A8. Clinical and Laboratory Standards Institute, Wayne, Pa, USA. 21. Promega BacTiter-Glo TM Microbial Cell Viability Assay. Technical Bulletin. Promega Corporation, Madison, Wi, USA. 22. Lowy FD Staphylococcus aureus infections. N. Engl. J. Med. 339: Watters AA, Jones RN, Leeds JA, Denys G, Sader HS, Fritsche TR Antimicrobial activity of a novel peptide deformylase inhibitor, LBM415, tested against respiratory tract and cutaneous infection pathogens: a global surveillance report ( ). J. Antimicrob. Chemother. 57: Credito K, Lin G, Ednie LM, Appelbaum PC Antistaphylococcal activity of LBM415, a new peptide deformylase inhibitor, compared with those of other agents. Antimicrob. Agents Chemother. 48: Bowker KE, Noel AR, MacGowan AP In vitro activities of nine peptide deformylase inhibitors and five comparator agents against respiratory and skin pathogens. Int. J. Antimicrob. Agents 22: Chen D, Hackbarth C, Ni ZJ, Wu C, Wang W, Jain R, He Y, Bracken K, Weidmann B, Patel DV, Trias J, White RJ, Yuan Z Peptide deformylase inhibitors as antibacterial agents: identification of VRC3375, a proline-3-alkylsuccinyl hydroxamate derivative, by using an integrated combinatorial and medicinal chemistry approach. Antimicrob. Agents Chemother. 48:
20 27. Osborne CS, Neckermann G, Fischer E, Pecanka R, Yu D, Manni K, Goldovitz J, Amaral K, Dzink-Fox J, Ryder NS In vivo characterization of the peptide deformylase inhibitor LBM415 in murine infection models. Antimicrob. Agents Chemother. 53: Adhikari RP, Novick RP Subinhibitory cerulenin inhibits staphylococcal exoprotein production by blocking transcription rather than by blocking secretion. Microbiology 151: Gemmell CG, Ford CW Virulence factor expression by Gram-positive cocci exposed to subinhibitory concentrations of linezolid. J. Antimicrob. Chemother. 50: Ohlsen K, Ziebuhr W, Koller KP, Hell W, Wichelhaus TA, Hacker J Effects of subinhibitory concentrations of antibiotics on alpha-toxin (hla) gene expression of methicillin-sensitive and methicillin-resistant Staphylococcus aureus isolates. Antimicrob. Agents Chemother. 42: Proctor RA, Olbrantz PJ, Mosher DF Subinhibitory concentrations of antibiotics alter fibronectin binding to Staphylococcus aureus. Antimicrob. Agents Chemother. 24: Rasigade JP, Moulay A, Lhoste Y, Tristan A, Bes M, Vandenesch F, Etienne J, Lina G, Laurent F, Dumitrescu O Impact of sub-inhibitory antibiotics on fibronectin-mediated host cell adhesion and invasion by Staphylococcus aureus. BMC Microbiol. 11: Kaplan JB Antibiotic-induced biofilm formation. Int. J. Artif. Organs 34:
21 34. Haddadin RN, Saleh S, Al-Adham IS, Buultjens TE, Collier PJ The effect of subminimal inhibitory concentrations of antibiotics on virulence factors expressed by Staphylococcus aureus biofilms. J. Appl. Microbiol. 108:
22 FIGURE LEGENDS Fig. 1. GSK oral pharmacokinetics and efficacy in a murine groin infection model at 150 mg/kg. (A) Blood concentration of free GSK after oral administration of 150 mg/kg in mice. Dotted lines mark the concentration corresponding to the GSK MIC for the different S. aureus strains used in the efficacy study. (B). Bacterial counts recovered from groins of infected mice. Animals (6 per group) were infected with different S. aureus strains at x 10 6 CFU/mouse. One hour after infection, a group of animals (NTC) were euthanized to determine bacterial counts at start of treatment. The other two groups were treated twice a day for 4 days with vehicle (C) or with 150 mg/kg of GSK (T). Mean +/- standard deviation is indicated by black lines. Fig 2. S. aureus growth curve studies. (A) Growth curve of S. aureus in the presence of variable amounts of GSK The study was completed as two separate experiments with samples taken at time points 0 10 hours on day 1 and at time points hours on day 2. (B) Growth curves of S. aureus PK2 in the presence of different antibiotics Fig. 3. Number of strains with >95% growth inhibited for 6 hours in the presence of GSK , linezolid or moxifloxacin. Fig. 4. Relationship between GSK MIC and fraction of MIC necessary to inhibit >95% growth of S. aureus strains for 6 hours
23 Table 1. Fraction/Multiple of MIC of different antibiotics inhibiting 95% growth of S. aureus, S. pneumoniae and H. influenzae strains for 6 hours Fraction/Multiple of MIC (MIC, g/ml) Antibiotic S. aureus PK Newman X32601 GSK /16 (4) 1/8 (4) 1/16 (4) 1/8 (2) GSK /16 (2) 1/32 (4) 1/8 (2) 1/8 (1) Actinonin 1/16 (32) 1/16 (32) 1/32 (64) 1/8 (16) Amikacin 1/2 (4) 1/2 (8) 1 (4) 1/2 (32) Amoxicillin 1/4 (4) 1/4 (32) 1 (0.25) 1 (128) Azithromycin* ND (>64) 1/2 (64) 1/4 (0.5) ND (>64) Linezolid 1/4 (2) 1/4 (2) 1/4 (2) 1/4 (2) Moxifloxacin 2 (0.03) 1 (0.06) 2 (0.03) 1/2 (8) Mupirocin 1/2 (0.5) 1/4 (0.5) 1/8 (1) 1/2 (1) Rifampicin 1/4 (0.016) 1/2 (0.016) 1/4 (0.016) 1/2 (0.008) Tetracycline 1/4 (0.5) 2 (32) 1/32 (2) 1/4 (16) Trimethoprim 1 (1) 1/2 (64) 2 (0.5) 1 (0.5) Vancomycin 1/2 (1) 1/2 (1) 1/2 (2) 1 (2) Antibiotic S. pneumoniae 1629 Ery S ATCC6303 GSK /4 (0.5) 1 (0.25) 1/2 (0.125) 1/2 (0.125) Moxifloxacin 1/2 (0.125) 2 (0.125) 2 (0.06) 1/2 (0.125) Antibiotic H. influenzae H L317/3 H128 GSK (2) 1/2 (1) 1 (0.5) 1/2 (1) Moxifloxacin 2 (4) 2 (0.016) 2 (0.016) 2 (0.008) * Two strains were resistant to azithromycin ND, Not done
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