The spread of multidrug resistance among major causative

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1 Comparative Analysis of the Antibacterial Activity of a Novel Peptide Deformylase Inhibitor, GSK Karen O Dwyer, a Meredith Hackel, b Sarah Hightower, a Daryl Hoban, b Samuel Bouchillon, b Donghui Qin, a Kelly Aubart, a Magdalena Zalacain, a * Deborah Butler a Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA a ; International Health Management Associates, Inc., Schaumburg, Illinois, USA b GSK is a novel peptide deformylase (PDF) inhibitor being developed for the intravenous and oral treatment of acute bacterial skin and skin structure infections and hospitalized patients with community-acquired pneumonia. The activity of GSK was tested against a global collection of clinical isolates of Haemophilus influenzae (n 2,370), Moraxella catarrhalis (n 115), Streptococcus pneumoniae (n 947), Streptococcus pyogenes (n 617), and Staphylococcus aureus (n 940), including strains resistant to one or more marketed antibiotics. GSK had an MIC 90 of 1 g/ml against M. catarrhalis and 4 g/ml against H. influenzae, with 88.8% of -lactamase-positive strains showing growth inhibition at that concentration. All S. pneumoniae strains were inhibited by <4 g/ml of GSK , with an MIC 90 of 2 g/ml. Pre-existing resistance mechanisms did not affect its potency, as evidenced by the MIC 90 of 1 g/ml for penicillin, levofloxacin, and macrolide-resistant S. pneumoniae. GSK was very potent against S. pyogenes strains, with an MIC 90 of 0.5 g/ml, irrespective of their macrolide resistance phenotype. This PDF inhibitor was also active against S. aureus strains regardless of their susceptibility to methicillin, macrolides, or levofloxacin, with an MIC 90 of 4 g/ml in all cases. Time-kill studies showed that GSK had bactericidal activity against S. pneumoniae, H. influenzae, S. pyogenes, and S. aureus, demonstrating a >3-log 10 decrease in the number of CFU/ml at 4 MIC within 24 h in 29 of the 33 strains tested. Given the antibacterial potency demonstrated against this panel of organisms, GSK represents a valuable alternative therapy for the treatment of infectious diseases caused by drug-resistant pathogens. The spread of multidrug resistance among major causative agents of skin and skin structure infections (SSSI) and community-acquired pneumonia (CAP) in hospitalized patients, such as Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, and Streptococcus pyogenes, has become a serious public health concern. S. pneumoniae resistance to -lactams, macrolides, tetracyclines, and trimethoprim-sulfamethoxazole (TMP-SMX) was reported as a worldwide problem in the early 2000s (1), and in 2008, 28% of the 40,000 cases of invasive infections reported in the United States were caused by a strain resistant to at least one drug and 11% were caused by a multidrugresistant S. pneumoniae strain (2). H. influenzae has developed resistance not only to -lactams (1) but also to tetracyclines, chloramphenicol, and TMP-SMX (3), and there are reservations about the clinical efficacy of macrolides (4). The level of macrolide-resistant S. pyogenes, the least common but deadliest of these pathogens, is variable, with an overall rate of 6 to 7% in the United States (5, 6) and 3 to 31% in Europe (7). In the case of S. aureus, the number of invasive infections caused by methicillin-resistant S. aureus (MRSA) is high in the hospital setting (8) and is increasing in the community (9). The appearance of MRSA strains resistant to cephalosporins, tetracyclines, sulfur drugs, and quinolones has reduced the list of treatment options for this serious pathogen. Hospitalizations associated with drug-resistant infections have considerable implications for the health care system compared to susceptible infections, including an increased risk of patient death and higher hospital costs and lengths of stay. In fact, on the basis of a 2009 study, the medical costs attributable only to MRSA infections in the United States were estimated to exceed $900 million a year (10). New treatment options, particularly those with oral and intravenous formulations appropriate for both adult and pediatric populations, are critically needed. Peptide deformylase (PDF), a metalloprotease that removes the N-formyl group present in all newly synthesized bacterial polypeptides (11 13), plays an essential role in protein maturation and is a highly conserved broad-spectrum target (14 17). PDF inhibitors therefore represent a new type of antibacterial agent with a novel mode of action and provide an alternative for the treatment of hospitalized patients with CAP and SSSIs caused by pathogens resistant to current therapies. The design of PDF inhibitors for potential clinical use has been the subject of research in a number of laboratories over the past decade, partly inspired by the discovery that actinonin, a naturally occurring antibacterial agent, is an inhibitor of PDF (18, 19). A large number of chemically diverse PDF inhibitors have been discovered through these efforts, and compounds with good antibacterial activity and in vivo efficacy have been reported (20). BB (21) and LBM415 (22) also progressed to phase I clinical trials, although they were not further developed. GSK (Fig. 1), a novel PDF inhibi- Received 19 December 2012 Returned for modification 4 February 2013 Accepted 2 March 2013 Published ahead of print 11 March 2013 Address correspondence to Deborah Butler, Deborah.L.Butler@gsk.com. * Present address: Magdalena Zalacain, Zala Drug Discovery Consulting LLC, West Chester, Pennsylvania, USA. Copyright 2013, American Society for Microbiology. All Rights Reserved. doi: /aac May 2013 Volume 57 Number 5 Antimicrobial Agents and Chemotherapy p aac.asm.org 2333

2 O Dwyer et al. FIG 1 Chemical structure of GSK tor of the hydrazide class, has shown good safety and pharmacokinetic properties in a phase I clinical trial and promising proofof-concept results in a phase IIa study ( GSK is currently being developed for the oral and intravenous treatment of acute bacterial SSSI and hospitalized patients with CAP. In this report, we summarize the spectrum of activity of GSK and selected comparator agents against a worldwide collection of H. influenzae, M. catarrhalis, S. pneumoniae, S. aureus, and S. pyogenes strains. In addition, we analyze the cell-killing activity of GSK with respect to that of other commonly used antibiotics. MATERIALS AND METHODS Bacterial strains. The organisms (4,989 strains) used in this study included 2,370 H. influenzae (517 -lactamase-positive), 115 M. catarrhalis, 947 S. pneumoniae (230 penicillin-intermediate, 165 penicillin-resistant, 329 macrolide-resistant, and 45 levofloxacin-resistant), 940 S. aureus (414 methicillin-resistant, 482 macrolide-resistant, and 308 levofloxacin-resistant), and 617 S. pyogenes (62 macrolide-resistant) strains. All study organisms were clinical strains isolated from 2006 through 2008 and frozen at 70 C, with the exception of the H. influenzae strains that were collected from 2001 through H. influenzae, S. pneumoniae, and M. catarrhalis were from community-associated respiratory tract infections (RTIs) from a multinational population, one isolate per patient. S. aureus isolates were 66% community associated and 34% hospital associated, 238 strains from RTIs and 702 strains from SSSIs. S. pyogenes isolates were all community associated, 65% from RTIs and 35% from SSSIs. Fifty-four percent of the study isolates were obtained from sites in North America, with an additional 32% from 23 European countries. The remaining 14% were divided among 24 other countries. Antimicrobial agents and susceptibility testing. GSK , obtained from GlaxoSmithKline Pharmaceuticals (Collegeville, PA) was dissolved in dimethyl sulfoxide and then further diluted 1:10 in sterile water to make a working stock solution. The antibacterial agents used for comparative analysis included amoxicillin, azithromycin, ceftriaxone, clindamycin, levofloxacin, linezolid, penicillin, tigecycline, and vancomycin and were provided by their manufacturers in the United States or by Fluka (Buchs, Switzerland) or Sigma Pharmaceuticals, LLC (Monticello, IA). Antibiotics were solubilized in the appropriate solvents as recommended by their respective manufacturers. Each resulting solution was further diluted in the appropriate broth medium for the sequential dilutions used in the broth microdilution panels. MIC endpoints were determined by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) guidelines (23). Cation-adjusted Mueller-Hinton (CAMH) broth was used for S. aureus and M. catarrhalis, with 3% lysed horse blood added for S. pneumoniae and S. pyogenes. Haemophilus test medium (HTM) broth was used for H. influenzae. Testing was performed with panels freshly prepared on the day of testing. Beta-lactamase testing of all H. influenzae and S. aureus isolates was performed by the cefinase disk methodology (Nitrocef Disks, Hardy Diagnostics). Methicillin phenotypes were determined for all S. aureus isolates with cefoxitin disks (30 g). Colonies were taken directly from a second-pass culture plate and prepared as a suspension equivalent to a 0.5 McFarland standard with normal saline. Inoculation of MIC plates took place within 15 min after adjustment of the inoculum suspension turbidity. Trays were incubated at 35 C for 20 to 24 h, except for S. aureus and M. catarrhalis, which were incubated for 16 to 20 h before the MIC endpoints were read. Quality control testing was performed on each day of testing as specified by CLSI, with the following isolates: S. pneumoniae ATCC 49619, S. aureus ATCC 29213, and H. influenzae ATCC and ATCC MIC 50 s, MIC 90 s, and MIC ranges were determined for all of the antimicrobial agents tested. Resistance phenotypes were defined by susceptibility to the corresponding antimicrobial agent according to CLSI interpretive criteria (24). Methicillin phenotypes were defined on the basis of the susceptibility results of the cefoxitin disk test. Macrolide phenotypes were based on azithromycin susceptibility. Time-kill studies. Time-kill studies were conducted to assess the inhibitory activity of GSK compared to that of linezolid, moxifloxacin, or azithromycin, depending on the organism. Seven strains of S. pneumoniae, eight strains of H. influenzae, and nine strains of S. aureus and S. pyogenes were used in this study. All isolates were obtained from the GSK Anti-Infectives culture collection. S. pneumoniae and S. aureus strains were cultured on Trypticase soy agar (TSA) with 5% sheep blood or in CAMH broth. S. pneumoniae strains were grown in Todd-Hewitt broth with yeast extract for inoculum preparation. H. influenzae strains were cultured on Chocolate II agar plates or in HTM broth. S. pyogenes strains were grown on TSA with 5% sheep blood or on MH broth with 3% lysed horse blood broth. Compounds were diluted into 20 ml of broth in a 50-ml Erlenmeyer flask to give final concentrations of 4 and 10 MIC for each organismcompound combination. For each isolate, a control flask containing no compound was also prepared. Cells from a second-pass plate were used to inoculate broth and grown to mid-logarithmic phase. The appropriate amount of inoculum was added to the prewarmed 20-ml broth-compound solutions and the drug-free controls to achieve a final concentration of CFU/ml. In order to minimize the occurrence of resistance to GSK in S. aureus by inactivation of formyl-methionyl transferase (FMT) (16), which could potentially affect the interpretation of results, the inoculum in this case was reduced to CFU/ml and recovered organisms were assessed for FMT mutant characteristics (T. Lewandowski, J. Huang, F. Fan, S, Rogers, D. Gentry, R. Holland, P. De- Marsh, K. Aubart, and M. Zalacain, submitted for publication). Flasks were placed on a shaker at 35 C, and viable counts were determined at 0, 2, 4, 6, 8, 10, 12, and 24 h by plating three 20- l aliquots of 10-fold serial dilutions of 100 l from each flask onto agar plates. The plates were incubated overnight at 35 C, and counts were determined at the dilution that provided distinguishable colonies. An average of the three aliquots was used to estimate the number of CFU in the original sample. In order to minimize the possibility of an inhibitory effect of the compound during growth on the agar plate, one 20- l aliquot was taken from the flask, diluted 5-fold into appropriate broth, and spread onto a plate, starting at4h(8hfors. aureus). For S. aureus only, at 10 h onward, this was done three times for each sample to lower the limit of detection from 50 to 16 CFU/ml. The levels of bacterial killing by the different compounds were determined by the log 10 decrease in the number of CFU/ml achieved after a specific incubation time with respect to the original inoculum. Strains were grouped according to their log 10 values. Group 1 contained strains that showed 1- and 2-log 10 decreases in the number of CFU/ml ( 90% but 99% killing). Group 2 contained strains that showed 2- and 3-log 10 decreases in the number of CFU/ml ( 99% but 99.9% killing). Group 3 contained strains that showed 3-log 10 decreases in the number of CFU/ml ( 99.9% killing). A compound was considered bactericidal at a specific time and multiple of the MIC if there was a 2334 aac.asm.org Antimicrobial Agents and Chemotherapy

3 Antibacterial Activity of GSK TABLE 1 Summary of antimicrobial activities of GSK at individual MICs Cumulative % of strains inhibited by GSK at MIC ( g/ml) of: Organism or phenotype (no. of isolates) All H. influenzae (2,370) Lactamase-positive H. influenzae (517) M. catarrhalis (115) S. pneumoniae (947) Penicillin resistant (165) Levofloxacin resistant (45) Macrolide resistant (329) S. aureus (940) MRSA (414) Levofloxacin resistant (308) Macrolide resistant (482) RTI (238) SSSI (702) S. pyogenes (617) Macrolide resistant (62) RTI (218) SSSI (399) a MIC 50 s are in italics. MIC 90 s are in bold. 3-log 10 decrease in the number of CFU/ml with respect to the original inoculum (25). A reduction of 3 log 10 CFU/ml was considered a bacteriostatic effect. In those studies where counts were reduced to the limit of detection and represented a 2.5-log 10 decrease in the number of CFU/ ml, the effect was considered to be bactericidal. RESULTS Overall antimicrobial activity of GSK The novel PDF inhibitor GSK showed good antibacterial activity against common RTI and SSSI pathogens (Table 1). GSK had an MIC 90 of 1 g/ml against M. catarrhalis and of 4 g/ml against H. influenzae, with 88.8% of the -lactamase positive strains showing growth inhibition at that concentration. The growth of 88% of the S. pneumoniae strains tested was inhibited by 1 g/ml of GSK , and 98.7% of them could not grow at 2 g/ml. In fact, 1 g/ml prevented the growth of 97, 93, and 91% of the penicillin-, levofloxacin-, and macrolide-resistant S. pneumoniae strains, respectively. Over 80% of the S. aureus strains analyzed were inhibited by GSK at 2 g/ml, and over 95% were inhibited by 4 g/ml, regardless of their phenotypes of resistance to other marketed antibiotics. This molecule also showed potent activity against S. pyogenes, with the growth of 48.8% of the strains inhibited by 0.25 g/ml and that of nearly 100% of the strains inhibited by 1 g/ml. GSK showed similar potency against isolates of S. aureus or S. pyogenes, irrespective of their RTI or SSSI origin. Antibacterial activity of GSK against Gram-negative pathogens. The activity of GSK was tested against 2,370 H. influenzae isolates of which 20% were resistant to ampicillin (Table 2). Beta-lactamase-negative strains had GSK MIC 50 and MIC 90 values of 2 and 4 g/ml, respectively, whereas for -lactamase-positive strains, those values were 2 and 8 g/ml, respectively (Table 2). Over 99% of the strains were susceptible to azithromycin and levofloxacin, with MIC 90 values of 2 and 0.03 g/ml, respectively, against this panel of organisms. The GSK MIC 90 for M. catarrhalis (115 isolates) was 1 g/ml, compared to 0.06 g/ml for azithromycin and levofloxacin and 2 g/ml for clindamycin (Table 2). Antibacterial activity of GSK against Gram-positive pathogens. The activities of GSK and a number of marketed antibiotics against S. pneumoniae (947 strains), S. pyogenes (617 strains), and S. aureus (940 strains) were tested (Table 3). All GSK MICs were 4 g/ml for S. pneumoniae, with MIC 50 and MIC 90 values of 1 and 2 g/ml, respectively. Pre-existing resistance mechanisms did not affect the potency of this compound, as evidenced by an MIC 90 for penicillin-, levofloxacin-, and macrolide-resistant S. pneumoniae of 1 g/ml. The activity of comparator antibiotics varied, and while 95% of the strains were still susceptible to ceftriaxone and levofloxacin, 17% of the strains were resistant to penicillin, 19% were resistant to clindamycin, and nearly 35% were resistant to azithromycin. This PDF inhibitor was also consistently active against all S. aureus strains, regardless of their susceptibility to methicillin, macrolides, or levofloxacin, with MIC 50 and MIC 90 values of 2 and 4 g/ml, respectively, in all cases. Linezolid and vancomycin, with MIC 90 of 4 and 1 g/ml, respectively, were the only two comparator agents fully effective against this panel of organisms. Resistance to all other antibiotics tested was high and translated into MIC 90 values of 4 g/ml for clindamycin, 8 g/ml for azithromycin and levofloxacin, 16 g/ml for ampicillin, and 64 g/ml for ceftriaxone. GSK was very potent against S. pyogenes strains, with both MIC 50 and MIC 90 values of 0.5 g/ml. No difference in activity was observed between macrolide-susceptible and -resistant strains or with the source of isolation. Comparator antibiotics were effective against these S. pyogenes strains, with susceptibilities ranging from 90% for azithromycin to nearly 100% for levofloxacin. May 2013 Volume 57 Number 5 aac.asm.org 2335

4 O Dwyer et al. TABLE 2 Antibacterial activities of GSK and selected comparators against a global collection of H. influenzae and M. catarrhalis strains MIC ( g/ml) Organism (no. of isolates) and drug 50% 90% Range % Susceptible a % Resistant a All H. influenzae (2,370) GSK b Ampicillin Azithromycin Levofloxacin Lactamase-negative H. influenzae (1,853) GSK Ampicillin Azithromycin Levofloxacin Lactamase-positive H. influenzae (517) GSK Ampicillin c Azithromycin Levofloxacin M. catarrhalis (115) GSK Azithromycin Clindamycin Levofloxacin a Susceptibility criteria of CLSI. For interpretation of M. catarrhalis results, breakpoints for H. influenzae were used. b No criteria have been established. c Based on -lactamase test. Time-kill analysis of GSK A summary of the cellkilling activities of GSK and comparative agents against different H. influenzae, S. pneumoniae, S. aureus, and S. pyogenes strains is presented in Table 4. GSK showed bactericidal activity by 24 h at both 4 and 10 MIC against all eight H. influenzae strains tested. Azithromycin also showed bactericidal activity against all of the strains at 10 MIC and against six of eight strains at 4 MIC. Regrowth was observed with this antibiotic after 24 h in seven of eight strains treated with 4 MIC and in two of eight strains treated with 10 MIC, but it was not due to development of resistance. Moxifloxacin was bactericidal against all of the strains at both concentrations by 24 h. In fact, this antibiotic reduced growth by more than 3 log 10 by8hinfiveofeight strains at both 4 and 10 MIC. Bactericidal activity was observed with GSK at 4 MIC within 24 h for six of the seven S. pneumoniae strains tested, as well as significant cell-killing activity against the last strain (2.66-log 10 decrease in cell numbers with respect to the baseline). At 10 MIC, GSK was bactericidal against all of the strains tested. Linezolid was bactericidal for all of the strains at both concentrations within 24 h, and moxifloxacin showed a very rapid cell-killing effect, with bactericidal activity in all cases within 8hat4 MIC and within4hat10 MIC. Time-kill analysis of GSK against nine strains of S. aureus showed that this PDF inhibitor was bactericidal within 24 h for seven of the nine organisms at 4 and 10 MIC. In general, cell-killing activity was slow, with counts decreasing over time and a full bactericidal effect seen at 12 or 24 h. In contrast, linezolid was clearly bacteriostatic against all of the strains in this study, with eight of nine strains showing 2-log 10 decreases in cell counts at 24 h at both 4 and 10 MIC and eight or six of the nine strains displaying a 1-log 10 reduction in bacterial counts at 12 h at 4 or 10 MIC, respectively. Moxifloxacin at 4 MIC was rapidly bactericidal against the four strains tested, with cell counts dropping to the limit of detection within 4 h. GSK was bactericidal at 4 MIC by 24 h versus eight of the nine S. pyogenes strains tested. Linezolid showed bactericidal activity against five of nine strains at 4 MIC and six of nine strains at 10 MIC within 24 h, and moxifloxacin was bactericidal within 24 h against all of the strains tested and within 8 h against seven of nine and eight of nine at 4 and 10 MIC, respectively. DISCUSSION With the appearance of resistance to most marketed antibiotics in all bacterial pathogens causing serious human diseases, the need for new therapies has become a pressing reality. The development of new agents against previously unexploited targets provides the additional advantage of avoiding potential cross-resistance to antibiotics already in use. One such target is PDF. PDF is ubiquitous in bacteria, where it plays an essential role in protein maturation, as removal of the N-formyl group is an indispensable step prior to the cleavage of the methionine residue by methionine aminopeptidase in the majority of newly synthesized proteins (26, 27). Deformylation is not necessary in eukaryotic cytoplasmic protein synthesis, and although a mitochondrial PDF has been identified (28), it is much less active than its bacterial counterpart, even when N-formylated peptides corresponding to the N-terminal sequence of human mitochondrial proteins are used as the substrate (29). Thus, inhibitors of PDF can be broad spectrum, selective 2336 aac.asm.org Antimicrobial Agents and Chemotherapy

5 Antibacterial Activity of GSK TABLE 3 Antimicrobial activities of GSK and selected comparators against Gram-positive organisms Organism, phenotype, or source MIC ( g/ml) (no. of isolates) and drug 50% 90% Range % Susceptible a % Resistance a S. pneumoniae (947) GSK b Azithromycin Ceftriaxone Clindamycin Levofloxacin Penicillin Penicillin susceptible (552) GSK Azithromycin Ceftriaxone Clindamycin Levofloxacin Penicillin Penicillin intermediate (230) GSK Azithromycin Ceftriaxone Clindamycin Levofloxacin Penicillin Penicillin resistant (165) GSK Azithromycin Ceftriaxone Clindamycin Levofloxacin Penicillin Levofloxacin susceptible (900) GSK Azithromycin Ceftriaxone Clindamycin Levofloxacin Penicillin Levofloxacin resistant (45) GSK Azithromycin Ceftriaxone Clindamycin Levofloxacin Penicillin Macrolide susceptible (609) GSK Azithromycin Ceftriaxone Clindamycin Levofloxacin Penicillin Macrolide resistant (329) GSK Azithromycin Ceftriaxone Clindamycin Levofloxacin Penicillin (Continued on following page) May 2013 Volume 57 Number 5 aac.asm.org 2337

6 O Dwyer et al. TABLE 3 (Continued) Organism, phenotype, or source MIC ( g/ml) (no. of isolates) and drug 50% 90% Range % Susceptible a % Resistance a MDR c (153), GSK S. aureus (940) GSK Ampicillin Azithromycin Ceftriaxone Clindamycin Levofloxacin Linezolid Tigecycline MSSA (526) GSK Ampicillin Azithromycin Ceftriaxone Clindamycin Levofloxacin Linezolid Tigecycline MRSA(414) GSK Ampicillin d 100 d Azithromycin Ceftriaxone d 100 d Clindamycin Levofloxacin Linezolid Tigecycline Vancomycin Levofloxacin susceptible (628) GSK Ampicillin Azithromycin Ceftriaxone Clindamycin Levofloxacin Linezolid Tigecycline Levofloxacin resistant (308) GSK Ampicillin Azithromycin Ceftriaxone Clindamycin Levofloxacin Linezolid Tigecycline Vancomycin Macrolide susceptible (456) GSK Ampicillin (Continued on following page) 2338 aac.asm.org Antimicrobial Agents and Chemotherapy

7 Antibacterial Activity of GSK TABLE 3 (Continued) Organism, phenotype, or source MIC ( g/ml) (no. of isolates) and drug 50% 90% Range % Susceptible a % Resistance a Azithromycin Ceftriaxone Clindamycin Levofloxacin Linezolid Tigecycline Macrolide resistant (482) GSK Ampicillin Azithromycin Ceftriaxone Clindamycin Levofloxacin Linezolid Tigecycline Vancomycin RTI (238) GSK Ampicillin Azithromycin Ceftriaxone Clindamycin Levofloxacin Linezolid Tigecycline SSSI (702) GSK Ampicillin Azithromycin Ceftriaxone Clindamycin Levofloxacin Linezolid Tigecycline S. pyogenes (617) GSK Azithromycin Clindamycin Levofloxacin Macrolide susceptible (555) GSK Azithromycin Clindamycin Levofloxacin Macrolide resistant (62) GSK Azithromycin Clindamycin Levofloxacin (Continued on following page) May 2013 Volume 57 Number 5 aac.asm.org 2339

8 O Dwyer et al. TABLE 3 (Continued) Organism, phenotype, or source MIC ( g/ml) (no. of isolates) and drug 50% 90% Range % Susceptible a % Resistance a RTI (218) GSK Azithromycin Clindamycin Levofloxacin SSSI (399) GSK Azithromycin Ceftriaxone Clindamycin Levofloxacin Linezolid Penicillin a Susceptibility criteria of CLSI. No criterion has been established. Strains resistant to two or more antibiotic classes. Based upon oxacillin susceptibility results (27). antibacterial agents not affected by pre-existing resistance mechanisms. The fact that PDF is amenable to X-ray crystallography (30) has facilitated the combination of classical screening methods with a more rational structure-based design approach in the discovery of novel PDF inhibitors. As a result, a considerable number of chemically diverse series of potent PDF inhibitors has been reported over the years, containing both peptidic and nonpeptidic scaffolds, with various antibacterial activities and in vivo efficacies in animal models of infection (20). Moreover, two pseudopeptidic PDF inhibitors, BB (21) and LBM415 (22), showed pharmacokinetic and toxicologic properties that supported their progression to phase I clinical trials. GSK , a nonpeptidic PDF inhibitor from the hydrazide family that is structurally distinct from the previous molecules, has successfully demonstrated safety and efficacy in human proof-of-concept clinical studies (http: // GSK is being progressed as an oral and intravenous agent for the treatment of acute bacterial SSSI and hospitalized patients with CAP and is currently in phase IIb clinical trials. The study reported here, assessing the in vitro activity of GSK against a large international collection of clinical isolates, demonstrates that the compound has potent antibacterial activity against key respiratory and skin pathogens, including those resistant to penicillin, methicillin, azithromycin, and levofloxacin. GSK shows an MIC 90 of 2 g/ml for S. pneumoniae, 4 g/ml for H. influenzae and S. aureus, 1 g/ml for M. catarrhalis, and 0.5 g/ml for S. pyogenes and demonstrates excellent activity against resistant organisms. In fact, the GSK MIC 90 for 165 penicillin-resistant, 329 macrolide-resistant, and 45 levofloxacin-resistant S. pneumoniae strain sets is 1 g/ml, including some strains that are resistant to more than one comparator antibiotic. For example, 7.9%, 11.5%, 58.2%, and 84.2% of the penicillin-resistant S. pneumoniae strains are also resistant to ceftriaxone, levofloxacin, clindamycin, or azithromycin, respectively. Equally, a percentage of the 329 macrolide-resistant strains are nonsusceptible to ceftriaxone (4.3%), levofloxacin (8.5%), or penicillin (42.2%) and 7.9% of them are resistant to azithromycin, penicillin, and ceftriaxone or levofloxacin. GSK s MIC 90 is 4 g/ml for 414 methicillin-resistant, 308 levofloxacin-resistant, and 482 macrolide-resistant S. aureus strains. Most MRSA strains are also resistant to azithromycin (88.2%), levofloxacin (65.7%), or ceftriaxone (28.5%). In fact, 52.7% of MRSA isolates are nonsusceptible to two of these antibiotics and 38.9% are resistant to all of them. Nearly 100% of the strains are susceptible to linezolid, which has an MIC 90 of 4 g/ml, and vancomycin is effective in all cases, with an MIC 90 of 1 g/ml. Curiously, perhaps as a reflection of the antibiotic therapy used to treat both infections, resistance to ceftriaxone, clindamycin, and levofloxacin seems to be more prevalent within the set of RTI strains than among the SSSI strains, while the levels of ampicillin and azithromycin resistance are similar among both the RTI and SSSI isolates. The activity of GSK against S. pyogenes, including the 62 macrolide-resistant strains tested, is similar to that of levofloxacin, with MIC 90 s of 0.5 and 1 g/ml, respectively. The resistance phenotype of the S. pyogenes strains tested is not affected by the source of the isolates. The growth of 94.2% of the -lactamase-negative and 88.8% of the -lactamase-producing H. influenzae strains was suppressed by 4 g/ml of GSK Of the organisms tested, the weakest activity and the widest range of MICs observed were against H. influenzae, probably because of the presence of efflux pumps, which have been shown to affect susceptibility to PDF inhibitors (22). Although the efficacy of this compound against H. influenzae strains with MICs of 4 to 8 g/ml has been demonstrated in RTI animal models (T. Lewandowski, unpublished data), pharmacokinetic/pharmacodynamic studies are necessary to provide additional information on the potential effectiveness of GSK in the clinic. Time-kill studies show that GSK is slowly bactericidal against S. pneumoniae, H. influenzae, S. pyogenes, and S. aureus, demonstrating a 3-log 10 decrease in the number of CFU/ml at 4 MIC within 24 h in 29 of the 33 strains tested. The activity is comparable to that of linezolid in S. pneumoniae, where moxi aac.asm.org Antimicrobial Agents and Chemotherapy

9 Antibacterial Activity of GSK TABLE 4 Cell-killing activities of GSK and comparator antibiotics at different multiples of their MICs against H. influenzae, S. pneumoniae, S. aureus, and S. pyogenes strains e No. of strains with indicated level of killing a at Organism (no. of strains), drug (MIC range [ g/ml]), and multiple of MIC 4h h h h H. influenzae (8) GSK (0.5 8) Azithromycin (0.25 4) b 6 b 6 b Moxifloxacin ( ) S. pneumoniae (7) GSK ( ) Linezolid (0.5 2) Moxifloxacin ( ) S. aureus (9) GSK (0.25 4) c 3 c 1 c 8 c 7 c 7 c Linezolid (2 4) Moxifloxacin d (0.06 4) S. pyogenes (9) GSK ( ) Linezolid (1 4) Moxifloxacin ( ) a Killing levels: 1, 90% but 99%; 2, 99% but 99.9%; 3, 99.9%. b Regrowth, not due to resistance, observed in two strains. c Regrowth of S. aureus FMT mutant observed in one strain. d Only four strains were used in this study. e Bold values denote a bactericidal effect against a number of strains at the times specified. Mean starting inoculum concentrations (CFU/ml) used: H. influenzae, ; S. pneumoniae, ; S. aureus, ; S. pyogenes, May 2013 Volume 57 Number 5 aac.asm.org 2341

10 O Dwyer et al. floxacin shows a very fast killing effect. In H. influenzae, the cellkilling activity is similar to that of azithromycin and only slightly slower than that of moxifloxacin. GSK shows more cellkilling activity than linezolid against S. pyogenes and S. aureus,as linezolid is bacteriostatic against four of the nine S. pyogenes strains and all of the S. aureus strains tested. Moxifloxacin, on the other hand, shows a much faster killing effect than GSK against both organisms. These results are similar to those observed with the PDF inhibitor LBM415 in H. influenzae (31) and S. pneumoniae (32). However, GSK seems to demonstrate more of a bactericidal effect against S. aureus than previously reported for LBM415 (22, 33) and is clearly differentiated from linezolid. In summary, GSK has the spectrum of activity and in vitro potency necessary for therapeutic use against respiratory tract and skin and soft tissue infections. Furthermore, its unique mode of action provides a clear advantage in the treatment of multidrug-resistant pathogens and ensures lack of cross-resistance with any other marketed antibiotics. This PDF inhibitor has completed early clinical trials and has shown pharmacokinetic and safety parameters warranting progression to phase IIb studies ( If clinically efficacious, GSK will provide a much-needed alternative therapy for the treatment of hospitalized patients with multidrug-resistant infections caused by the bacterial pathogens described in this report. REFERENCES 1. Jacobs MR, Felmingham D, Appelbaum PC, Gruneberg RN The Alexander Project : susceptibility of pathogens isolated from community-acquired respiratory tract infection to commonly used antimicrobial agents. J. Antimicrob. Chemother. 52: Centers for Disease Control and Prevention ABCs report: Streptococcus pneumoniae, Active Bacterial Core surveillance (ABCs): emerging infections program network. Centers for Disease Control and Prevention, Atlanta, GA. /spneu08.html. 3. Tristram S, Jacobs MR, Appelbaum PC Antimicrobial resistance in Haemophilus influenzae. Clin. Microbiol. Rev. 20: Jacobs MR Optimisation of antimicrobial therapy using pharmacokinetic and pharmacodynamic parameters. Clin. Microbiol. Infect. 7: Green MD, Beall B, Marcon MJ, Allen CH, Bradley JS, Dashefsky B, Gilsdorf JR, Schutze GE, Smith C, Walter EB, Martin JM, Edwards KM, Barbadora KA, Wald ER Multicentre surveillance of the prevalence and molecular epidemiology of macrolide resistance among pharyngeal isolates of group A streptococci in the USA. J. Antimicrob. Chemother. 57: Richter SS, Heilmann KP, Beekmann SE, Miller NJ, Miller AL, Rice CL, Doern CD, Reid SD, Doern GV Macrolide-resistant Streptococcus pyogenes in the United States, Clin. Infect. Dis. 41: Bandak SI, Turnak MR, Allen BS, Bolzon LD, Preston DA Oral antimicrobial susceptibilities of Streptococcus pyogenes recently isolated in five countries. Int. J. Clin. Pract. 54: Klevens RM, Edwards JR, Tenover FC, McDonald LC, Horan T, Gaynes R Changes in the epidemiology of methicillin-resistant Staphylococcus aureus in intensive care units in US hospitals, Clin. Infect. Dis. 42: Klevens RM, Morrison MA, Nadle J, Petit S, Gershman K, Ray S, Harrison LH, Lynfield R, Dumyati G, Townes JM, Craig AS, Zell ER, Fosheim GE, McDougal LK, Carey RB, Fridkin SK Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 298: Roberts RR, Hota B, Ahmad I, Scott RD, II, Foster SD, Abbasi F, Schabowski S, Kampe LM, Ciavarella GG, Supino M, Naples J, Cordell R, Levy SB, Weinstein RA Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin. Infect. Dis. 49: 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: 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: Chen DZ, Patel DV, Hackbarth CJ, Wang W, Dreyer G, Young DC, Margolis PS, Wu C, Ni ZJ, Trias J, White RJ, Yuan Z Actinonin, a naturally occurring antibacterial agent, is a potent deformylase inhibitor. Biochemistry 39: Apfel C, Banner DW, Bur D, Dietz M, Hirata T, Hubschwerlen C, Locher H, Page MG, Pirson W, Rosse G, Specklin JL Hydroxamic acid derivatives as potent peptide deformylase inhibitors and antibacterial agents. J. Med. Chem. 43: 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: Clinical and Laboratory Standards Institute Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 8th ed. Approved standard M07-A8. Clinical and Laboratory Standards Institute, Wayne, PA. 24. Clinical and Laboratory Standards Institute Performance standards for antimicrobial susceptibility testing; 19th informational supplement, M100-S19. Clinical Laboratory Standards Institute, Wayne, PA. 25. Clinical and Laboratory Standards Institute Methods for determining bactericidal activity of antimicrobial agents. Approved guideline M26-A. Clinical and Laboratory Standards Institute, Wayne, PA. 26. Meinnel T, Mechulam Y, Blanquet S Methionine as translation start signal: a review of the enzymes of the pathway in Escherichia coli. Biochimie 75: Solbiati J, Chapman-Smith A, Miller JL, Miller CG, Cronan JE, Jr Processing of the N termini of nascent polypeptide chains requires deformylation prior to methionine removal. J. Mol. Biol. 290: Serero A, Giglione C, Meinnel T Distinctive features of the two classes of eukaryotic peptide deformylases. J. Mol. Biol. 314: Nguyen KT, Hu X, Colton C, Chakrabarti R, Zhu MX, Pei D Characterization of a human peptide deformylase: implications for antibacterial drug design. Biochemistry 42: Smith KJ, Petit CM, Aubart K, Smyth M, McManus E, Jones J, Fosberry A, Lewis C, Lonetto M, Christensen SB Structural variation and inhibitor binding in polypeptide deformylase from four different bacterial species. Protein Sci. 12: Bogdanovich T, Smith KA, Clark C, Pankuch GA, Lin G, McGhee P, Dewasse B, Appelbaum PC Activity of LBM415 compared to those of 11 other agents against Haemophilus species. Antimicrob. Agents Chemother. 50: Ednie LM, Pankuch G, Appelbaum PC Antipneumococcal activity of LBM415, a new peptide deformylase inhibitor, compared with those of other agents. Antimicrob. Agents Chemother. 48: 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: aac.asm.org Antimicrobial Agents and Chemotherapy

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