Novel monobactams utilizing a siderophore uptake mechanism for the treatment of gram-negative infections

Article abstract of DOI:10.1016/j.bmcl.2012.07.005

Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MDR Gram-negative pathogens are described.

Full text of DOI:10.1016/j.bmcl.2012.07.005

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5989–5994
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel monobactams utilizing a siderophore uptake mechanism for the
treatment of gram-negative infections
Mark J. Mitton-Fry a, Joel T. Arcari a, Matthew F. Brown a, , Jeffrey M. Casavant a, Steven M. Finegan c,
⇑
Mark E. Flanagan a, Hongying Gao d, David M. George c, Brian S. Gerstenberger a, Seungil Han e,
Joel R. Hardink d, Thomas M. Harris a, Thuy Hoang a, Michael D. Huband c, Rebecca Irvine c,
Manjinder S. Lall a, M. Megan Lemmon c, Chao Li a, Jian Lin d, Sandra P. McCurdy c, John P. Mueller c,
Lisa Mullins c, Mark Niosi d, Mark C. Noe a, David Pattavina f, Joseph Penzien c, Mark S. Plummer a,
Hud Risley a, Brandon P. Schuff a, Veerabahu Shanmugasundaram b, Jeremy T. Starr a, Jianmin Sun a,
Jennifer Winton d, Jennifer A. Young a
a Medicinal Chemistry, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA
b Computational Chemistry, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA
c Antibacterials Research Unit, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA
d Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA
e Structural Biology, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA
f Analytical R&D;Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MDR
Gram-negative pathogens are described.
Received 18 May 2012
Revised 27 June 2012
Accepted 2 July 2012
Available online 20 July 2012
Ó 2012 Published by Elsevier Ltd.
Keywords:
Monobactam
Gram-negative
Pseudomonas aeruginosa
Klebsiella pneumoniae
Escherichia coli
Siderophore
MC-1
Multidrug resistance (MDR) to antibacterial agents, particularly
among Gram-negative pathogens, represents a serious and growing
threat to human health.1 Simultaneously, we are approaching a cri-
sis with regard to the development of new antibiotics, so continued
research in the area is desperately needed.1,2 We recently disclosed
a series of novel antibacterial compounds incorporating a monocar-
bam nucleus conjugated to a siderophore moiety, including MC-1
(1, Fig. 1) and its 4-methyl analog (2).3 Other researchers have also
recently described compelling work in the area of siderophore-con-
jugated b-lactams, most particularly with BAL197644 and
BAL300725 (3). Herein, we report additional efforts targeting MDR
Gram-negative pathogens with a series of novel siderophore-conju-
gated monobactams, represented generically by 4. This work has
culminated in the identification of numerous analogs with potent
MIC90 values against three clinically important pathogens, Pseudo-
monas aeruginosa (P. aer.), Klebsiella pneumoniae (K. pneumo.), and
Escherichia coli (E. coli).
Gram-negative microorganisms have evolved a series of resis-
tance mechanisms which limit the utility of currently available
therapies.6 These mechanisms include barriers to drug penetration,
active efflux of compounds via a plethora of transporters, and en-
zymes such as bÀlactamases which catalyze the degradation of
certain therapies. New medicines capable of overcoming or cir-
cumventing these resistance mechanisms will prove useful in the
treatment of infections from MDR pathogens.7 Bacteria rely on
the acquisition of certain nutrients from the host in order to sur-
vive and have developed specialized mechanisms to facilitate these
processes. Among the most intriguing are mechanisms for iron
acquisition,8 in which bacteria manufacture and secrete iron
⇑
Corresponding author. Tel.: +1 860 441 3522.
E-mail address: matthew.f.brown@pfizer.com (M.F. Brown).
0960-894X/$ - see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.bmcl.2012.07.005

5990
M. J. Mitton-Fry et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5989–5994
O
OH
O
O
Me
Me
OH
OH
N
OH
O
O
Me
N
Me
N
O
O
O
O
O
O
OH
OH
N
O
H
N
H
N
H
N
Me
N
R
O
N
N
H2N
Me
X
L
N
R
N
O
H2N
N
H
H2N
H
N
N
N
O
N
N
S
S
N
S
S
O
O
OSO3H
O
SO3H
O
OH
HO
1
3
4
: X = O, NH; R = H, OH, L = variable
: R = H (MC-1)
(BAL30072)
2: R = Me
Figure 1. Siderophore-conjugated monocyclic b-lactams.
chelators known as siderophores.8,9 The organisms then utilize
specialized transport systems for the reuptake of these sidero-
phores and subsequently utilize the acquired iron. Conjugation of
siderophore mimics to drugs such as b-lactams enables active
delivery of the antibacterial moiety to the bacteria by exploiting
the siderophore transport system, effectively a ‘Trojan Horse’
approach.10,11
Our efforts with monocarbams such as 1 capitalized effectively on
this strategy to deliver highly potent agents with promising Gram-
negative spectrum,3 remarkable stability to b-lactamases,12 and
in vivo efficacy in murine models of infection. One potential limita-
tion of monocarbams such as 1, however, is their sensitivity to aque-
ous hydrolysis. This issue is not unique to monocarbams. For
example, the carbapenem meropenem exhibited similar stability is-
sues in our hands.3 The enhanced stability shown by compounds
such as the 4-methyl analog 23 led us to consider investigation of sid-
erophore linkage to the 4-position of the b-lactam. Structural biology
efforts (vide infra) also suggested an opportunity for productive
exploration of SAR via this strategy, and we sought to develop robust
synthetic chemistry that would facilitate this understanding. In this
light, our interest was piqued by earlier work from Magerlein, who
demonstrated that catechol-containing esters such as 5 and 6
(Fig. 2) possessed both in vitro and in vivo activity against the key
pathogens of interest.13,14
Table 1
Minimum inhibitory concentrations (MICs) for sample organisms
Compound
MIC P. aer. 1091-05a
(
lg/mL)
MIC P. aer. 1042-06b
(lg/mL)
Aztreonam
6
7
8
2–4
0.5
1
32–64
32
16
32
0.5
0.25
4
1
9
0.125
0.25
4
0.5
8
13
14
15
16
1
32
a
1091-05 (UC12120) is a penicillin-resistant, quinolone-sensitive strain courtesy
of Bronson Methodist Hospital, Kalamazoo, MI.
b
1042-06 is a b-lactam- and quinolone-resistant, polymyxin B-sensitive skin/soft
tissue isolate courtesy of the British Society for Antimicrobial Chemotherapy
(BSAC).
additional work but also revealed poor activity against recent clin-
ical isolates of P.aer (Table 1).
In some instances, isobutyric acid-substitution of the oxime in
place of the acetic acid moiety found in 6 (i.e., –C(CH3)2– vs –
CH2–) can provide enhanced anti-Pseudomonal activity.16 Com-
pound 7 (Fig. 2) incorporates this strategy but failed to demonstrate
any meaningful improvements (Table 1).17 Catechol derivatives
have also been shown to undergo metabolism via catechol O-meth-
yltransferase,18,19 a liability which can hinder optimization of their
pharmacokinetic properties. However, 3-hydroxypyridin-4(1H)-
one (henceforward referred to as pyridone for simplicity) moieties
appear to circumvent this undesired metabolic pathway18,20 and
have been employed successfully as siderophore mimics in com-
pounds such as 1, U-78608,21 and pirazmonam (SQ-83,360).20
Work with cephalosporins also demonstrated the feasibility of
Analogs were tested for minimum inhibitory concentrations
(MICs) using a panel of organisms, including both drug-susceptible
strains (P.aer. 1091-05 is representative) and recent MDR clinical
isolates (P. aer. 1042-06 is representative). Particularly promising
analogs were also evaluated using broader panels of organisms in
order to determine MIC90 values,15 (concentration at which visible
growth of 90 percent of the strains is inhibited). Screening of 6 in
the initial panel revealed sufficiently compelling potency to justify
O
O
Me
OH
OH
OH
OH
Me
N
O
OH
O
O
OH
O
O
H
N
H
N
N
H
N
N
O
SO3H
7
N
H2N
O
L
H2N
N
O
O
S
N
S
O
O
SO3H
5: L is absent
: L = CH2NHC(O)
O
O
N
6
OH
OH
8 =
9 =
N
H
OH
Figure 2. Examples of precedented and novel siderophore-conjugated monobactams.

M. J. Mitton-Fry et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5989–5994
5991
1,3-dihydroxypyridones (henceforth N-hydroxypyridones),22and
this siderophore mimic has also been employed with BAL197644
and BAL300725 (3). Consequently, we prepared analogs 8 and 9.
Whereas 8 demonstrated comparable activity, while the MICs for
9 represented a surprising breakthrough.
Compound 9 was prepared according to Scheme 1. Acid 10 was
reacted with ethyl glycine to give the corresponding amide. Sapon-
ification and oxidation of the pyridine with urea hydrogen peroxide
(UHP) and trifluoroacetic anhydride provided acid 11, contami-
nated with a lesser amount of the unoxidized pyridine. Esterifica-
tion with the known alcohol 12,23 sulfonation24 and global
deprotection with BCl3 afforded the targeted compound in modest
yield. Similar chemistry was employed for related analogs.
Having demonstrated potent antimicrobial activity for 9, we
sought to evaluate progress against two principal design objec-
tives, aqueous stability and utilization of the iron-uptake pathway
for bacterial entry. The aqueous stability profile for 9 was similar to
the 4-methylated monocarbam 2 and thus helped build our confi-
dence in this strategy (Fig. 3). A mutant organism of K. pneumo.
with an abrogated TonB25 system (required for providing the en-
Figure 3. Aqueous stability data at room temperature for compounds 2 and 9.
ergy for siderophore active uptake) showed substantially poorer
MIC values relative to the wild-type strain (unpublished results).
A similar observation was made with a strain of P. aer. which car-
ried a mutated piuA, a TonB-dependent gene.26 These results
clearly demonstrate a dependence on the siderophore uptake path-
way. Profiling 9 against small panels of organisms revealed very
Me
CO2tBu
Me
O
N
H
N
N
OH
BocHN
O
NH
S
OBn
OBn
(12)
O
OBn
OBn
1. Ethyl 2-aminoacetate
HOBT, NEt3, DCC, DMF (67%)
1. HATU, NaHCO3,
DMF (48%)
O
H
N
HO
9
N
HO
N
O
2. H2O, NaOH, EtOH (98%)
3. UHP, TFAA, CH3CN, 0oC
2. DMF.SO3, DMF (97%)
3. BCl3, CH2Cl2, 0 deg. C
O
O
11
31%
10
Scheme 1. Synthesis of ester analog 9.
Table 2
MIC and MIC90 data for selected compounds
O
Me
OH
O
Me
N
O
O
OH
O
H
N
N
N
H
L
N
R
H2N
N
S
O
SO3H
N
N
L =
L =
L =
L = absent
R = OH (14)
R = H (16)
R = OH (15)
R = H (17)
R = H (18)
R = OH (19)
R = H (21)
N
O
O
S
Compound
MIC P. aer. 1091–05
g/mL)
MIC P. aer. 1042–06
g/mL)
P. aer. MIC90 (n = 51)
g/mL)
K. pneumo. MIC90 (n = 11) E. coli. MIC90 (n = 11)
g/mL) g/mL)
A. bau. MIC90 (n = 11)
g/mL)
(
l
(
l
(
l
(l
(l
(l
Meropenem 0.5
1
NT
0.5
8
0.5
0.25
0.125
0.5
0.5
0.5
2
>64
0.5*
4
2
1
0.25
0.5
1
1
2
32
8*
>64
32
2
16
16
32
8
4
2
ND
8
0.06
2*
16
1
0.125
1
4
1
1
1
64
0.125*
>64*
64
3
1
9
0.125
0.25
0.125–0.5
0.125
1
0.25
1
0.5
>64
>64
>64
16
>64
32
>64
16
ND
>64
13
19
20
21
22
23
24
25
26
0.5
>64
0.5
2
ND
1
0.5
ND
1
8
0.125
*
Data for 1 from literature using larger panel of organisms.3

5992
M. J. Mitton-Fry et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5989–5994
O
Me
OH
O
Me
N
O
O
OH
O
H
N
N
O
L
N
R
H2N
N
S
O
SO3H
N
N
L =
13
L =
15
R = H (
L =
16
R = H ( )
R = OH (
)
)
14
R = H (
)
N
O
N
S
Figure 4. Heteroaromatic ester-linked siderophore-conjugated monobactams.
i. THF, NCS then pyridine
ii. 60oC
OBn
OBn
N
OBn
N
1. DIBAL, THF
-78oC
OBn
OBn
OBn
iii. 0oC,
CO2Me
BnO
N
N
2. HONH2.HCl
NaOAc, MeOH
reflux
iv. NEt3 in THF, 5oC
N
HO
O
O
MeO2C
(73-79%, 2 steps)
81%
CH2Cl2
m-CPBA
0oC to rt
OBn
OBn
OBn
OBn
LiOH, THF
MeOH, H2O
N
N
N
O
N
O
O
O
HO2C
MeO2C
17 (86%)
76%
(contaminated with 2-3%
unoxidized pyridine)
Me
Me
CO2H
1. CH2Cl2, PPh3,
imidazole, I2 (78%)
CO2tBu
Me
N
Me
O
1. HATU, NaHCO3,
O
O
O
2. 2-Me-THF, NEt3, nBu4N3
D
DMF, (72%)
O
N
H
N
20-35oC (96%)
H
2. DMF.SO3, DMF (85%)
3. BCl3, CH2Cl2, 0oC
N
N
N
OH
N
H
NH2
H2N
12
BocHN
3. H2 (30 psi), Pd/C,
EtOH (97%)
N
O
N
O
NH
N
HO
S
S
O
SO3H
O
18
19
43%
Scheme 2. Enabling synthetic chemistry for amide analogs such as 19.
potent preliminary MIC90 values against both P.aer. and E. coli with
somewhat weaker activity against K. pneumo. and no notable po-
tency against Acinetobacter baumannii (Table 2). Compound 9 also
displayed favorable human protein binding (Fu = 0.57) and low
clearance in the rat after IV dosing (8.9 ml/min/kg). With this infor-
mation in hand, we sought to further optimize the properties of
compound 9, for example by improving upon the K. pneumo.
activity.
Polar heteroaromatic rings have previously been utilized suc-
cessfully as linkers between b-lactams and siderophore mimics.27
Replacement of the glycine linker in 9 with an isoxazole as in 13
(Fig. 4) greatly improved the K. pneumo. MIC90 while preserving
the broader Gram-negative spectrum. Consistent with our previous
experience, the analogous pyridone analog 14 displayed substan-
tially reduced potency. Replacement of the isoxazole in 14 with a
thiazole (15) resulted in intermediate activity, whereas replace-
ment with a pyrimidine (16) was highly deleterious. These efforts
established both the viability of the series and the ability to mod-
ulate attributes such as antimicrobial potency using different lin-
ker motifs.
Despite its compelling Gram-negative spectrum, compound 13
contains a potentially labile ester moiety and showed suboptimal
pharmacokinetic properties (vide infra). Given our concerns around
metabolic stability, we also prepared analogs containing an amide
Figure 5. Static time kill experiment with compound 19.

M. J. Mitton-Fry et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5989–5994
5993
linkage in place of the ester. The requisite 4-aminomethyl-substi-
tuted b-lactam intermediate 18 could be accessed from alcohol
12 via the corresponding azide as depicted in Scheme 2.
The amide series yielded a number of highly compelling ana-
logs. The isoxazole 19 (Scheme 2) proved more potent than ester
13 against P. aer., showed acceptable E. coli activity, and provided
somewhat diminished K. pneumo. potency (Table 2). A static con-
centration time kill experiment with P. aer. 1091-05 demonstrated
extremely rapid killing (Fig. 5).
Our group has previously reported X-ray crystallographic data
of the covalent complex of 1 and its primary biological target in
P. aer., penicillin binding protein 3 (PBP3).28 Biochemical assays
also showed 19 to be a potent inhibitor of PBP3 (data not shown),
and we aimed to better understand its binding mode through
structural studies. Comparing the crystal structures of 1 and 19
with PBP3, one notes substantial overlap of the homologous por-
tions of the analogs (Fig. 6). In addition, despite their differing
points of attachment to the bÀlactam nucleus, the siderophore
moieties are located in roughly similar positions. The linker moie-
ties adopt substantially different conformations in this relatively
large pocket, providing additional justification for continued ana-
log work in this series.
parators (19 and 20, respectively). A thiazole (23) also showed
promise. The simple amide 24 showed excellent spectrum and
demonstrated moderate activity against A. baumannii. In contrast,
the enantiomer of 24 (i.e., 25) showed greatly diminished activity,
consistent with literature precedent regarding the importance of
the stereochemistry at C3 of the lactam.29 The pyridone analog
(26) of N-hydroxypyridone 24 lacked appreciable MICs against A.
bau. and also showed reduced K. pneumo. activity.
Having identified a number of highly potent analogs as mea-
sured by in vitro activity, we sought additional means to prioritize
them for future study. Pharmacokinetic assessments in rat were
carried out using an intravenous dose of 1 mg/kg (Table 3). Like-
wise, the protein binding was evaluated using rat and human plas-
ma. Using these values to calculate unbound clearance in rat, it
appeared that the N-hydroxypyridone analogs in general provided
superior pharmacokinetic properties (20 vs 22 and 24 vs 26).
Amide 19 also showed substantially reduced clearance versus ester
13.
Selected compounds were also evaluated for efficacy using a
murine infection model of pneumonia with P. aer. 1091-05 (Table
4). ED50 values were determined on the basis of reductions in lung
colony forming unit (CFU) counts over the course of the study. As a
general rule, efficacy correlated well with intrinsic clearance in this
model, suggesting a reasonable linkage between pharmacokinetic
properties and efficacy. Compound 24 proved to be an exception,
as it under performed in vivo. Preliminary studies using static time
Other 5-membered heteroaryl analogs such as oxazole 20
(Table 2) also showed promise. In addition, we prepared pyridone
analogs (21 and 22). Somewhat surprisingly, these compounds
demonstrated roughly similar activity to their N–OH series com-
Figure 6. Crystal structure of Pseudomonas aeuroginosa PBP3 with monocarbam 1 (green) and monobactam 19 (orange). PBP3 backbone is shown in a ribbon representation
for reference. (A) 1 (open form) complexed with Pseudomonas aeuroginosa PBP3, (B) Overlay of bound conformations (ligands only) of 1 (green) and 19 (orange), (C) 19 (open
form) complexed with Pseudomonas aeuroginosa PBP3. (PDB deposition numbers: compound 1 (3PBT), compound 19 (4FSF)).
Table 3
Pharmacokinetic and protein binding data for selected compounds
Compound
Human plasma protein binding (Fu)
Rat plasma protein binding (Fu)
Rat plasma Cl (mL/min/kg)
Total
Unbound
9
13
19
20
21
22
23
24
26
0.57
0.32
0.46
0.80
0.31
0.30
0.08
0.44
0.54
0.36
0.24
0.33
0.25
0.26
0.073
0.03
0.58
0.66
8.9
34.7
8.1
9.1
15.7
8.8
19.6
8.0
46.6
24.7
144.6
24.5
36.4
60.4
120.5
653.3
13.8
70.6
Table 4
Murine pharmacokinetics and in vivo efficacy results for selected analogs
Compound
Mouse plasma protein binding (Fu)
Mouse Cl (ml/min/kg)
Mouse Cl,inta (ml/min/kg)
ED50 (mg/kg/dose)
19
20
22
24
0.65
0.99
0.42
0.80
34.7
21.9
34.7
30.6
86.97
29.29
134.60
58.06
73.6
34.7
>100
>100
a
total plasma clearance corrected for protein binding and mouse blood flow.

5994
M. J. Mitton-Fry et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5989–5994
12. Lacey, B. M.; Aschenbrenner, L. A.; McPherson, C. J.; Lemmon, M. M.; Penzien, J.
B.; Fahnoe, K. C.; Finegan, S. M.; Tadakamalla, B.; Huband, M. D.; O’Donnell, J.
P.; Miller, J. R.; Mueller, J. P.; Tomaras, A. P. 50th Interscience Conference on
Antimicrobial Agents and Chemotherapy, Abstract no. C1-657. American Society
for Microbiology, Washington, D.C.
kills (data not shown) suggest that this result may be due to a
greater propensity to elicit resistance.
In summary, we have presented a synthetically enabled series
of siderophore-conjugated monobactams with excellent in vitro
activity against MDR Gram-negative pathogens. Certain analogs
also possess favorable pharmacokinetic and in vivo efficacy proper-
ties. Additional efforts toward the optimization of this series will
be communicated in due course.
13. Magerlein, B. J. WO 90/03376 1990.
14. For additional work on catechol-containing 4-substituted monobactams, see:
Arnould, J. C.; Boutron, P.; Pasquet, M. J. Eur. J. Med. Chem. 1992, 27, 131.
15. Brown, M. F.; Gupta, R. R.; Kuhn, M.; Flanagan, M. E.; Mitton-Fry, M.
MedChemComm 2011, 2, 735.
16. Yoshida, C.; Tanaka, K.; Todo, Y.; Hattori, R.; Fukuoka, Y.; Komatsu, M.;
Saikawa, I. J. Antibiot. 1986, 39, 90.
References and notes
17. That replacement of the acetic acid moiety with an isobutyric moiety does not
prove advantageous also has precedent. See: Yamawaki, K.; Nomura, T.;
Yasukata, T.; Uotani, K.; Miwa, H.; Takeda, K.; Nishitani, Y. Bioorg. Med. Chem.
Lett. 2007, 15, 6716.
18. Mochida, K.; Ono, Y.; Yamasaki, M.; Shiraki, C.; Hirata, T.; Sato, K.; Okachi, R. J.
Antibiot. 1987, 40, 182.
19. Ohi, N.; Aoki, B.; Kuroki, T.; Matsumoto, M.; Kojima, K.; Nehashi, T. J. Antibiot.
1987, 40, 22.
20. Sykes, R. B.; Koster, W. H.; Bonner, D. P. J. Clin. Pharmacol. 1988, 28, 113.
21. (a) Barbachyn, M. R.; Tuominen, T. C. J. Antibiot. 1990, 43, 1199; (b) Zurenko, G.
E.; Truesdell, S. E.; Yagi, B. H.; Mourey, R. J.; Laborde, A. L. Antimicrob. Agents
Chemother. 1990, 34, 884.
22. Ogino, H.; Iwamatsu, K.; Katano, K.; Nakabayashi, S.; Yoshida, T.; Tsuruoka, T.;
Inouye, S.; Kondo, S. J. Antibiot. 1990, 43, 174.
23. Kim, K. S.; Chambers, J. H. J. Antibiot. 1987, 40, 124.
24. Floyd, D. M.; Fritz, A. W.; Pluscec, J.; Weaver, E. R.; Cimarusti, C. M. J. Org. Chem.
1982, 47, 5160.
1. Boucher, H. W.; Talbot, G. H.; Bradley, J. S.; Edwards, J. E.; Gilbert, D.; Rice, L. B.;
Scheld, M.; Spellberg, B.; Bartlett, J. Clin. Infect. Dis. 2009, 48, 1.
2. Cooper, M. A.; Schlaes, D. Nature 2011, 472, 32.
3. Flanagan, M.; Brickner, S.; Lall, M.; Casavant, J.; Deschenes, L.; Finegan, S.;
George, D.; Granskog, K.; Hardink, J.; Huband, M.; Hoang, T.; Lamb, L.; Marra,
A.; Mitton-Fry, M.; Mueller, J.; Mullins, L.; Noe, M.; O’Donnell, J.; Pattavina, D.;
Penzien, J.; Schuff, B.; Sun, J.; Whipple, D.; Young, J.; Gootz, T. ACS Med. Chem.
Lett. 2011, 2, 385.
4. (a) Livermore, D. M.; Mushtaq, S.; Warner, M. J. Antimicrob. Chemother. 2010, 65,
2382; (b) Page, M. G. P.; Dantier, C.; Desarbre, E.; Gaucher, B.; Gebhardt, K.;
Schmitt-Hoffmann, A. Antimicrob. Agents Chemother. 2011, 55, 1510.
5. (a) Page, M. G. P.; Dantier, C.; Desarbre, E. Antimicrob. Agents Chemother. 2010,
54, 2291; (b) Mushtaq, S.; Warner, M.; Livermore, D. J. Antimicrob. Chemother.
2010, 65, 266; (c) Russo, T. A.; Page, M. G. P.; Beanan, J. M.; Olson, R.; Hujer, K.
M.; Jacobs, M.; Bajaksouzian, S.; Endimiani, A.; Bonomo, R. A. J. Antimicrob.
Chemother. 2011, 66, 867.
25. Krewulak, K. D.; Vogel, H. J. Biochem. Cell Biol. 2011, 89, 87.
26. Cornelis, P.; Matthijs, S.; Van Oeffelen, L. Biometals 2009, 22, 15.
27. (a) Choi, K. I.; Cha, J. H.; Pae, A. N.; Cho, Y. S.; Kang, H-Y.; Koh, H. Y.; Chang, M.
H. J. Antibiot. 1995, 48, 1371; (b) Choi, K. I.; Cha, J. H.; Pae, A. N.; Cho, Y. S.; Kang,
H-Y.; Koh, H. Y.; Chang, M. H. J. Antibiot. 1995, 48, 1375.
6. Peleg, A. Y.; Hooper, D. C. N. Engl. J. Med. 1804, 2010, 362.
7. Bassetti, M.; Ginocchio, F.; Mikulska, M. Crit. Care 2011, 15, 215.
8. (a) Skaar, E. P. PLOS Pathogens 2010, 6, 1; (b) Hannauer, M.; Yeterian, E.; Martin,
L. W.; Lamont, I. L.; Schalk, I. J. FEBS Lett. 2010, 584, 4751.
28. Han, S.; Zaniewski, R. P.; Marr, E. S.; Lacey, B. M.; Tomaras, A. P.; Evdokimov, A.;
Miller, J. R.; Shanmugasundaram, V. Proc. Natl. Acad. Sci. 2010, 107, 22002.
29. Cimarusti, C. M.; Bonner, D. P.; Breuer, H.; Chang, H. W.; Fritz, A. W.; Floyd, D.
M.; Kissick, T. P.; Koster, W. H.; Kronenthal, D.; Massa, F.; Mueller, R. H.;
Pluscec, J.; Slusarchyk, W. A.; Sykes, R. B.; Taylor, M.; Weaver, E. R. Tetrahedron
1983, 39, 2577.
9. (a) Cornelis, P. Appl. Microbiol. Biotechnol. 2010, 86, 1637; (b) Miethke, M.;
Marahiel, M. A. Microbiol. Mol. Biol. Rev. 2007, 71, 413; (c) Hider, R. C.; Kong, X.
Nat. Prod. Rep. 2010, 27, 637.
10. Budzikiewicz, H. Curr. Topics Med. Chem. 2001, 1, 73–82.
11. (a) Page, M. G. P.; Heim, J. I. Drugs 2009, 12, 561; (b) Moellmann, U.; Heinisch,
L.; Bauernfeind, A.; Koehler, T.; Ankel-Fuchs, D. Biometals 2009, 22, 615.