An Unsaturated Quinolone N-Oxide of Pseudomonas aeruginosa Modulates Growth and Virulence of Staphylococcus aureus

Article abstract of DOI:10.1002/anie.201702944

The pathogen Pseudomonas aeruginosa produces over 50 different quinolones, 16 of which belong to the class of 2-alkyl-4-quinolone N-oxides (AQNOs) with various chain lengths and degrees of saturation. We present the first synthesis of a previously proposed unsaturated compound that is confirmed to be present in culture extracts of P. aeruginosa, and its structure is shown to be trans-Δ¹-2-(non-1-enyl)-4-quinolone N-oxide. This compound is the most active agent against S. aureus, including MRSA strains, by more than one order of magnitude whereas its cis isomer is inactive. At lower concentrations, the compound induces small-colony variants of S. aureus, reduces the virulence by inhibiting hemolysis, and inhibits nitrate reductase activity under anaerobic conditions. These studies suggest that this unsaturated AQNO is one of the major agents that are used by P. aeruginosa to modulate competing bacterial species.

Full text of DOI:10.1002/anie.201702944

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201702944
German Edition: DOI: 10.1002/ange.201702944
Inhibitors Hot Paper
An Unsaturated Quinolone N-Oxide of Pseudomonas aeruginosa
Modulates Growth and Virulence of Staphylococcus aureus
Dꢀvid Szamosvꢀri and Thomas Bçttcher*
Abstract: The pathogen Pseudomonas aeruginosa produces
over 50 different quinolones, 16 of which belong to the class of
HHQ and PQS and are derived from a common biosynthetic
[6]
precursor (Figure 1). The various AQNOs differ mainly in
the length and saturation of their alkyl chains. Of these
compounds, only 2-heptyl-4-quinolone N-oxide (HQNO)
2
-alkyl-4-quinolone N-oxides (AQNOs) with various chain
lengths and degrees of saturation. We present the first synthesis
of a previously proposed unsaturated compound that is
confirmed to be present in culture extracts of P. aeruginosa,
and, to
a lesser extent, 2-nonyl-4-quinolone N-oxide
1
and its structure is shown to be trans-D -2-(non-1-enyl)-4-
quinolone N-oxide. This compound is the most active agent
against S. aureus, including MRSA strains, by more than one
order of magnitude whereas its cis isomer is inactive. At lower
concentrations, the compound induces small-colony variants
of S. aureus, reduces the virulence by inhibiting hemolysis, and
inhibits nitrate reductase activity under anaerobic conditions.
These studies suggest that this unsaturated AQNO is one of the
major agents that are used by P. aeruginosa to modulate
competing bacterial species.
Figure 1. Different roles of the diverse quinolones of P. aeruginosa. The
HHQ- and PQS-type quinolones are known as quorum sensing signals
to coordinate population-density-dependent behavior. In contrast,
AQNOs are considered as antibacterial compounds with moderate
activity against S. aureus.
S
ynergistic and antagonistic interactions of microorganisms
are important factors that shape microbial communities and
[
1]
may decide over health or disease of their human host. The
opportunistic human pathogens Pseudomonas aeruginosa and
Staphylococcus aureus are both capable of causing a broad
variety of diseases, ranging from simple skin infections to life-
threatening sepsis and endocarditis. Both species are fre-
quently involved in polymicrobial infections where they
engage in a broad range of interactions with major impact
[
7]
(NQNO) have been studied in greater detail. HQNO was
reported to moderately inhibit the growth of S. aureus and is
able to select for metabolically impaired small-colony var-
iants on agar plates by blocking the electron transport chain
[8]
through cytochrome b inhibition.
A recent study used low-resolution mass spectrometry to
identify 56 alkylquinolone derivatives, including sixteen
AQNOs of P. aeruginosa, and to quantify their corresponding
concentrations in culture media. Some of the reported
AQNOs are produced in several milligrams per liter whereas
others are only present in concentrations that are orders of
[2]
on the development and progression of infectious diseases.
Most frequently, however, the interactions of P. aeruginosa
and S. aureus have been described as being of competitive
[9]
[
3]
nature. Cystic fibrosis patients are initially colonized
prevalently by S. aureus, which in later stages is largely
replaced by P. aeruginosa although neither species completely
[
9,10]
magnitude lower.
It remained unknown, however,
[
2,3b]
disappears during any stage of the chronic disease.
It has
whether this structural diversity is correlated with different
biological activities or functions. The three most abundant
AQNOs that were detected included two saturated N-oxides
with heptyl and nonyl chains as well as one unsaturated
compound with a nonenyl group. The structure of the latter
compound has been assigned based on mass spectrometry
only, and fragmentation patterns led to the conclusion that the
double bound was likely located between the a- and
b-positions of the side chain. The configuration of the
double bond, however, could not be assigned but only one
configuration has been suggested to be the major constitu-
recently been demonstrated that P. aeruginosa contributes to
the eradication of Staphylococcus by manipulating the innate
[
4]
immunity of the host. In addition, P. aeruginosa also directly
produces antibacterial factors that have been implicated in
targeting and inhibiting competitors such as S. aureus. These
factors comprise pyocyanin, cyanide, and 2-alkyl-4-quinolone
[
9]
[5]
N-oxides. The 2-alkyl-4-quinolone N-oxides (AQNOs) are
structurally related to the quinolone quorum sensing signals
[*] D. Szamosvꢀri, Dr. T. Bçttcher
[9]
ent.
Fachbereich Chemie, Konstanz Research School Chemical Biology,
Zukunftskolleg
Universitꢁt Konstanz, 78457 Konstanz (Germany)
E-mail: Thomas.Boettcher@uni-konstanz.de
We thus aimed to develop a strategy for the synthesis of
both isomers of the proposed unsaturated compound to
elucidate the configuration at the double bond of the native
metabolite. We also synthesized all other major and two
minor AQNOs along with the corresponding 2-alkyl-4-
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.201702944.
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
quinolones (AQs) of P. aeruginosa for a comparative inves-
tigation of their activities against S. aureus.
For saturated compounds, an efficient synthetic strategy
has been described previously and could be adapted to the
native chain-length derivatives with pentyl (PQNO), heptyl
Cyclization of 2e in a Camps reaction as described by Carrie
[
13]
and co-workers gave (E)-2-(non-1-en-1-yl)quinolin-4-one
(3e) in 20% yield over three steps (Scheme 1B). The same
strategy failed for the cis analogue as significant isomerization
of the double bond was observed during the amide coupling
reaction of 2’-aminoacetophenone and the acid chloride of
(Z)-dec-2-enoic acid (1g; see the Supporting Information).
Therefore, dec-2-ynoic acid (1 f) was synthesized by Jones
oxidation of 2-decyn-1-ol and coupled to 2-aminoacetophe-
none to give dec-2-ynamide 2 f, which was afterwards
stereoselectively reduced with the Lindlar catalyst to give
(Z)-N-(2-acetylphenyl)dec-2-enamide (2g). The Z amide 2g
was eventually cyclized to (Z)-2-(non-1-en-1-yl)quinolin-4-
one (3 f) in a Camps reaction (Scheme 1C). Further con-
version of the unsaturated AQs 3e and 3 f was achieved in
analogy to the saturated compounds by ethyl carbonate
protection (4e and 4 f), N oxidation (5e and 5 f), and
deprotection to afford the corresponding N-oxides 6e and
6 f. Thus our library comprised twelve compounds with six
AQNOs (6a–f) and the corresponding AQs (3a–f).
[
11]
(
HQNO), nonyl (NQNO), and undecyl (UQNO) residues.
In a first step, we prepared 3-oxoalkanoic acid methyl esters
a–d from the corresponding acyl chlorides with Meldrumꢀs
acid. Condensation with aniline led to methyl-3-phenylamino-
-enoates 2a–d, which were subsequently subjected to
1
2
Conrad–Limpach cyclization into the 2-alkylquinolones 3a–
d. The AQs were locked in a single tautomer as ethyl
carbonates (4a–d), which was followed by N oxidation with
[
12]
mCPBA as described by Woschek and co-workers.
The
resulting ethyl carbonate N-oxides 5a–d were deprotected to
yield the corresponding AQNOs 6a–d. Their analytic data
suggest that they are present in the 4-quinolone tautomeric
form (Scheme 1A).
1
For the synthesis of unsaturated AQNOs (cis/trans-D -
NQNO), a different strategy was employed that involves the
generation of N-(2-acetylphenyl) alkyl amides followed by
Camps cyclization to the quinolones and subsequent N ox-
idation. To obtain the most abundant unsaturated AQNO in
trans configuration, we synthesized (E)-dec-2-enoic acid (1e)
from octanal and malonic acid. Condensation of the acid
chloride of 1e with 2’-aminoacetophenone gave amide 2e.
These compounds were then used as synthetic standards
to confirm the production of the corresponding AQNOs and
AQs in culture supernatants of P. aeruginosa by comparing
the retention times of the extracted ion chromatograms of
high-resolution mass spectra. Extracts of the culture super-
natants of the two virulent clinical P. aeruginosa strains PA14
and PAO1 revealed three
major N-oxides, namely the
saturated compounds HQNO
(
6b) and NQNO (6c) and an
1
unsaturated D -NQNO, which
is in accordance with the liter-
[
9]
ature. Thus LC-MS methods
were optimized to separate the
cis and trans isomers (Fig-
ure 2A; see also the Support-
ing Information, Figures S1
and S2). Interestingly, only
1
trans-D -NQNO was found
1
whereas cis-D -NQNO was
not detected. The other satu-
rated AQNOs were only
detected in trace amounts
(6a) or were even below the
detection limit (6d). Very sim-
ilar relative ratios were also
found for the corresponding
AQs, with 3b, 3c, and 3e being
the most abundant (Fig-
ure S3).
Next, we were interested in
investigating the antibacterial
activity of the compounds in
liquid cultures of four different
strains of S. aureus including
MRSA. An initial screening at
2
00 mm, at which the com-
Scheme 1. Synthesis of AQs and AQNOs. A) Strategy towards saturated AQs and AQNOs with different
chain lengths. Synthesis of B) trans-D -NQ (3e), C) cis-D -NQ (3 f), and their corresponding N-oxides (6e
and 6 f).
1
1
pounds were still soluble,
revealed that after 24 h incu-
2
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
was fully inhibited (incubated for 24 h with 150 mm 6e) into
fresh medium without any AQNO. In this case, growth was
restored within 24 to 48 h, indicating bacteriostatic activity.
HQNO has been described as an inhibitor of the respiratory
chain, which typically leads to the induction of small colony
variants (SCVs) in S. aureus on agar plates. A dose-down
1
experiment confirmed that trans-D -NQNO 6e and NQNO
6
c also induced SCVs down to 3.125 nmol whereas the
1
corresponding cis-D -NQNO 6 f did not induce SCVs at the
highest dose tested (25 nmol, Figure 3A). SVCs have been
Figure 2. Production and activity of AQNOs. A) LC-HRMS analysis for
a–6 f in PAO1 extracts. The base peak chromatogram is given in gray
6
with the extracted ion chromatograms for 6a–6 f superimposed. EICs
of the synthetic standards (intensity-adjusted) are given at the top in
black. B) Representative growth inhibition experiments with 6e and 6 f
with the MRSA strain USA300 in well plates at 200 mm (top) and by
the disc diffusion method on agar with 25 nmol compound (bottom).
1
C) Growth curves of S. aureus USA300 with trans-D -NQNO (6e), its
Figure 3. Effects of AQNOs on metabolism and virulence of S. aureus.
A) Induction of small-colony variants of S. aureus NCTC 8325–4 at
12.5 nmol by 6c and 6e but not by 6 f. B) Inhibition of hemolysis of
S. aureus USA300 on blood agar. C) Testing for nitrate reductase
activity after different incubation times with culture densities given by
the OD600 values.
1
saturated version (6c), and trans-D -NQ (3e) as mean values of
triplicates.
bation, none of the AQs (3a-3 f) had inhibited growth and
also most AQNOs had not resulted in complete growth
inhibition (Table S1). The saturated NQNO (6c) was only
slightly active with an MIC of 200 mm. All other saturated
compounds including HQNO (6b) were inactive under these
described to be in an altered metabolic state where their
ability for quorum sensing via the agr system is compro-
1
[14]
conditions. However, the unsaturated trans-D -NQNO (6e)
mised.
The majority of S. aureus virulence factors are
was highly active against all strains with MIC values of 10–
coordinated via agr, and we were thus curious if at sub-growth
inhibitory concentrations, AQNOs may inhibit virulence. We
used the hemolytic activity of S. aureus as a readout for the
production of erythrocyte-disrupting a- and b-toxins as major
virulence factors. Whereas application of the saturated
À1
1
2
5 mm (3–7 mgmL ). In contrast, isomeric cis-D -NQNO (6 f)
did not result in growth inhibition even at 200 mm in liquid
cultures and did not inhibit growth in a plate diffusion assay at
2
5 nmol, at which the trans isomer produced a clear zone of
1
inhibition (Figure 2B). These results indicate a highly specific
NQNO 6c only resulted in incomplete inhibition, trans-D -
interaction of the trans isomer with its target. The unprece-
dented high activity of trans-D -NQNO (6e) raised the
NQNO 6e fully inhibited hemolysis already at 25 nmol
(Figures 3B and S4).
1
question as to how it compares to other antibacterial
compounds produced by P. aeruginosa. We tested pyocyanin
as one of the major antibacterial metabolites of P. aeruginosa
and obtained an MIC of 50 mm for the different strains of
It has been suggested that HQNO inhibits the respiratory
[
8b,15]
chain via cytochrome b.
While the architecture of the
respiratory chain of S. aureus is thus far only incompletely
understood, there are multiple instances where HQNO has
been applied in protein crystallization to mimic the native
1
S. aureus, demonstrating that trans-D -NQNO is even more
[
16]
potent than pyocyanin by a factor of two to five (Table S1).
To obtain more detailed insight into the growth inhibition,
menaquinone ligand in oxidoreductase enzymes. Although
these enzymes did not include a closely related homologue of
components of the respiratory chain of S. aureus, it may be
speculated that AQNOs are generally capable of blocking the
menaquinone-binding sites of various different enzymes. To
investigate this possibility, we selected the nitrate reductase
activity, which is exhibited by S. aureus under anaerobic
conditions. To this aim, S. aureus was inoculated at high cell
density in anaerobic nitrate-rich medium with either 5 mm
1
we measured growth curves for NQNO (6c), trans-D -
1
NQNOs (6e), and trans-D -NQ (3e) for the epidemic
MRSA strain USA300 (Figure 2C). With compound 6e, no
growth was seen at 10 mm, and growth only slowly restarted at
5
mm and 2.5 mm with a prolonged lag phase, while 6c only
incompletely inhibited growth at 100 mm. In contrast, the
1
trans-D -NQ did not significantly inhibit growth, pointing
1
again to the importance of the N-oxide group for activity. To
test if the antibacterial effect was bacteriostatic or bacter-
icidal, we diluted a culture of S. aureus Mu50 where growth
trans-D -NQNO 6e or DMSO. Whereas the DMSO control
clearly indicated formation of nitrite as detected with a diazo
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
dye, the samples treated with 6e did not indicate the presence
strategies of P. aeruginosa to control and modulate the
behavior of co-infecting bacteria to its own advantage.
Furthermore, the considerable differences in activity between
the three major AQNOs produced by P. aeruginosa suggest
possible functional differentiation with distinct yet unknown
roles for different AQNOs.
of nitrite at any time (Figure 3C and S5).
1
These results suggest that trans-D -NQNO 6e targets at
least two distinct pathways, namely the respiratory chain
under aerobic conditions and the nitrate reductase activity
under anaerobic conditions. We thus propose a model in
which 6e mimics the redox couple menaquinone/menaquinol
and thereby inhibits different menaquinone-dependent
enzymes (Figures 4A and S6). This inhibition leads to Acknowledgements
We thank Prof. Andreas Marx and his group for their
generous support. We gratefully acknowledge funding by
the Emmy Noether program of the Deutsche Forschungsge-
meinschaft (DFG), a EU FP7 Marie Curie Zukunftskolleg
Incoming Fellowship Program (University of Konstanz Grant
2
91784), the Fonds der Chemischen Industrie (FCI), the
Konstanz Research School Chemical Biology (KoRS-CB),
and SFB969 (DFG). D.S. was supported by a KoRS-CB PhD
fellowship. We thank PD Dr. David Schleheck for use of their
S2 facilities and Prof. Bernhard Schink and Sylke Wiechmann
for an introduction into anaerobic culture techniques.
Conflict of interest
The authors declare no conflict of interest.
Keywords: AQNO · menaquinone analogue · MRSA ·
Pseudomonas aeruginosa · virulence inhibition
1
Figure 4. Proposed mode of action of AQNOs: trans-D -NQNO blocks
the respiratory chain by cytochrome b (cyt b) inhibition under aerobic
conditions and by nitrate reductase (Nar) inhibition under anaerobic
conditions. B) Redox cycling of native menaquinols (MK-n) and
[
[
[
1] B. M. Peters, M. A. Jabra-Rizk, G. A. OꢀMay, J. W. Costerton,
M. E. Shirtliff, Clin. Microbiol. Rev. 2012, 25, 193 – 213.
2] A. T. Nguyen, A. G. Oglesby-Sherrouse, Appl. Microbiol. Bio-
technol. 2016, 100, 6141 – 6148.
menaquinones (MKH -n) and comparison with the two tautomeric
2
1
forms of trans-D -NQNO (6e). In S. aureus, the typical menaquinones
are MK-7 and MK-8, but also MK-4, MK-5, MK-6, and MK-9 have been
[
17]
reported.
3] a) N. Nair, R. Biswas, F. Gotz, L. Biswas, Infect. Immun. 2014, 82,
2162 – 2169; b) R. Baldan, C. Cigana, F. Testa, I. Bianconi, M.
De Simone, D. Pellin, C. Di Serio, A. Bragonzi, D. M. Cirillo,
PLoS One 2014, 9, e89614.
4] E. Pernet, L. Guillemot, P. R. Burgel, C. Martin, G. Lambeau, I.
Sermet-Gaudelus, D. Sands, D. Leduc, P. C. Morand, L. Jeam-
met, M. Chignard, Y. Z. Wu, L. Touqui, Nat. Commun. 2014, 5,
pleiotropic effects, including growth inhibition at high con-
centrations, as well as the induction of small-colony variants
and inhibition of virulence at lower concentrations. We
[
1
speculate that the more rigid unsaturated trans-D -NQNO
5105.
6
e may be better suited than the saturated versions to mimic
[
5] a) L. M. Filkins, J. A. Graber, D. G. Olson, E. L. Dolben, L. R.
Lynd, S. Bhuju, G. A. OꢀToole, J. Bacteriol. 2015, 197, 2252 –
2264; b) L. Voggu, S. Schlag, R. Biswas, R. Rosenstein, C.
Rausch, F. Gotz, J. Bacteriol. 2006, 188, 8079 – 8086.
6] C. E. Dulcey, V. Dekimpe, D. A. Fauvelle, S. Milot, M. C.
Groleau, N. Doucet, L. G. Rahme, F. Lepine, E. Deziel, Chem.
Biol. 2013, 20, 1481 – 1491.
7] a) A. Fugꢁre, D. L. Sꢂguin, G. Mitchell, E. Deziel, V. Dekimpe,
A. M. Cantin, E. Frost, F. Malouin, PLoS One 2014, 9, e86705;
b) N. F. Baig, S. J. Dunham, N. Morales-Soto, J. D. Shrout, J. V.
Sweedler, P. W. Bohn, Analyst 2015, 140, 6544 – 6552; c) R.
Hazan, Y. A. Que, D. Maura, B. Strobel, P. A. Majcherczyk,
L. R. Hopper, D. J. Wilbur, T. N. Hreha, B. Barquera, L. G.
Rahme, Curr. Biol. 2016, 26, 195 – 206; d) A. T. Nguyen, J. W.
Jones, M. Camara, P. Williams, M. A. Kane, A. G. Oglesby-
Sherrouse, Front. Microbiol. 2016, 7, 1171.
the native ligands menaquinone or menaquinol in the
corresponding binding sites (Figure 4B). In contrast, the cis
double bond in 6 f introduces a kink into the structure that
may clash with the binding sites.
[
[
In conclusion, we have reported the first synthesis of
1
trans-D -NQNO and have confirmed that along with its
saturated counterparts, it is one of three major quinolone
N-oxides produced by P. aeruginosa strains. We demonstrated
1
that trans-D -NQNO exhibits up to 20-fold higher bacterio-
static activity against S. aureus strains than the most potent
saturated AQNO. This unprecedented activity makes trans-
1
D -NQNO a potential major player in cross-species interac-
tions during polymicrobial infections. Metabolic changes,
such as small-colony variant induction, or inhibition of nitrate
reduction as well as virulence inhibition may be combined
[
8] a) L. R. Hoffman, E. Deziel, D. A. D’Argenio, F. Lepine, J.
Emerson, S. McNamara, R. L. Gibson, B. W. Ramsey, S. I.
4
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
Miller, Proc. Natl. Acad. Sci. USA 2006, 103, 19890 – 19895;
B. C. Kahl, K. Becker, B. Loffler, G. Peters, Front. Cell. Infect.
b) J. W. Lightbown, F. L. Jackson, Biochem. J. 1956, 63, 130 – 137.
9] F. Lꢂpine, S. Milot, E. Dꢂziel, J. He, L. G. Rahme, J. Am. Soc.
Mass Spectrom. 2004, 15, 862 – 869.
Microbiol. 2014, 4, 99.
[
[15] A. I. Zatsman, H. Zhang, W. A. Gunderson, W. A. Cramer, M. P.
Hendrich, J. Am. Chem. Soc. 2006, 128, 14246 – 14247.
[16] a) T. M. Iverson, C. Luna-Chavez, L. R. Croal, G. Cecchini, D. C.
Rees, J. Biol. Chem. 2002, 277, 16124 – 16130; b) M. L. Rodri-
gues, K. A. Scott, M. S. Sansom, I. A. Pereira, M. Archer, J. Mol.
Biol. 2008, 381, 341 – 350; c) Y. Matsumoto, T. Tosha, A. V.
Pisliakov, T. Hino, H. Sugimoto, S. Nagano, Y. Sugita, Y. Shiro,
Nat. Struct. Mol. Biol. 2012, 19, 238 – 245.
[
10] E. Deziel, F. Lepine, S. Milot, J. He, M. N. Mindrinos, R. G.
Tompkins, L. G. Rahme, Proc. Natl. Acad. Sci. USA 2004, 101,
1339 – 1344.
[
[
[
[
11] D. Szamosvꢃri, F. V. Reichle, M. Jureschi, T. Bçttcher, Chem.
Commun. 2016, 52, 13440 – 13443.
12] A. Woschek, M. Mahout, K. Mereiter, F. Hammerschmidt,
Synthesis 2007, 1517 – 1522.
[17] M. D. Collins, D. Jones, Microbiol. Rev. 1981, 45, 316 – 354.
13] C. P. Jones, K. W. Anderson, S. L. Buchwald, J. Org. Chem. 2007,
72, 7968 – 7973.
14] a) B. C. Kahl, G. Belling, P. Becker, I. Chatterjee, K. Wardecki,
K. Hilgert, A. L. Cheung, G. Peters, M. Herrmann, Infect.
Immun. 2005, 73, 4119 – 4126; b) R. A. Proctor, A. Kriegeskorte,
Manuscript received: March 21, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
1
Inhibitors
Pseudomonas’ secret weapon: trans-D -2-
Nonenyl-4-quinolone N-oxide, the most
active quinolone N-oxide produced by
Pseudomonas aeruginosa against Staph-
ylococcus aureus, was synthesized. The
efficacy of this compound is also dem-
onstrated by its ability to inhibit the
hemolytic and nitrate reductase activity of
S. aureus at low concentrations. These
results shed new light onto how P. aeru-
ginosa chemically modulates the growth
and behavior of its competitors.
D. Szamosvꢁri,
T. Bçttcher*
&&&& — &&&&
An Unsaturated Quinolone N-Oxide of
Pseudomonas aeruginosa Modulates
Growth and Virulence of Staphylococcus
aureus
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!