INSIGHTS | PERSPECTIVES
690 17 FEBRUARY 2017 • VOL 355 ISSUE 6326
research efforts. But the last point will be
particularly challenging to address, because
there are hardly any ongoing programs
for the development of selective ARBP decolonization agents. Such agents would, in
contrast to therapeutic antibiotics, not act
systemically and leave most commensals in
ARBP decolonization can be successful,
as has been shown for nasal MRSA eradication with the antibiotic mupirocin in
surgical patients (6). However, mupirocin
resistance is now approaching 30% in some
parts of the United States (9) and Asia, demanding the development of alternative
drugs. Moreover, mupirocin is a broad-spectrum antibiotic that disrupts the entire
microbiota, thereby promoting horizontal
transfer of resistance genes and facilitating recolonization by ARBPs. Antibiotic
pressure may also result in amplification of
resistance genes in commensals, which can
later transfer these genes horizontally to
facultative pathogens (10).
Selective digestive decolonization (SDD)
regimes for targeting antibiotic-resistant
Gram-negative bacteria have been implemented in intensive care units (11). But, contrary to what its name suggests, SDD is not
selective. It often includes antibiotics of last
resort, such as colistin, widespread use of
which could increase resistance selection and
thus jeopardize the future of antibiotic therapies. Also, like mupirocin, colistin is a broad-spectrum antibiotic and therefore causes
the same problems with regard to resistance
transfer and recolonization as mupirocin.
Effective ARBP decolonization will require a conceptual change in anti-infective
drug development strategies, which are currently largely focused on broad-spectrum
antimicrobials (1) (see the figure). In contrast
to therapeutic antibiotics, decolonization
drugs should not be resorbed by epithelia
and should inhibit only a narrow spectrum
of pathogens. They may include small-molecule drugs that inhibit ARBP colonization and fitness—for example, by blocking
pathogen binding to epithelial receptors,
increasing susceptibility to mucosal host
defense, or disrupting bacterial signaling
mechanisms. Highly species-specific bacteriophages or bacteriophage-derived lytic
proteins combine nonresorbable properties
with narrow-spectrum bactericidal activity
(12). Moreover, commensal bacteria produce
narrow-spectrum antimicrobial molecules
called bacteriocins that may be helpful in the
development of decolonizing probiotics (13).
Fecal transplantation approaches may also
become important components of integrated
decolonization regimes (14).
However, many pharmaceutical compa-
nies have been reluctant to pursue narrow-
spectrum or decolonization agents because
of worries that such drugs may not have a
sufficient market potential to justify devel-
opment costs. It is high time to change this
notion, because the demands for effective
and sustainable decolonization regimes will
strongly increase in the near future. Mupiro-
cin, a generic drug, has reached annual sales
of more than $120 million (15). This drug has
disadvantages, such as its broad-spectrum ac-
tivity and the fact that it stops bacteria from
reproducing, rather than killing them. Nev-
ertheless, its high market volume indicates
that decolonization drugs can be economi-
cally viable. A large fall in severe ARBP in-
fections would reduce costs for intensive care
substantially, justifying the costs of ARBP
screening and decolonization.
New classes of broad-spectrum antibiotics will not become available in the next
few years. It will therefore be crucial to
strengthen efforts for preventing infections
due to ARBPs (1) by reevaluating infection
control measures, improving surveillance of
ARBP incidence in community and health
care settings, implementing alert systems
for early detection of new resistance patterns, and reducing unwarranted antibiotic
use in human and veterinary medicine.
Only by integrating these measures with
an innovative anti-infective strategy that
focuses not only on therapeutic agents but
also on decolonizing therapies can we avoid
a postantibiotic era. j
REFERENCES AND NOTES
1. R. Laxminarayan et al ., Lancet Infect. Dis. 13, 1057 (2013).
2. WHO, Antimicrobial resistance: Global report
on surveillance; http://apps.who.int/iris/bitstr
3. F. R. DeLeo, M. Otto, B. N. Kreiswirth, H. F. Chambers,
Lancet 375, 1557 (2010).
4. S. Karanika, T. Karantanos, M. Arvanitis, C. Grigoras,
E. Mylonakis, Clin. Infect. Dis. 63, 310 (2016).
5. C. J. Donskey, S. Kundrapu, A. Deshpande, Infect. Dis. Clin.
N. Am. 29, 13 (2015).
6. L. G. Bode et al. , N. Engl. J. Med. 362, 9 (2010).
7. M.J.Vehreschild etal.,
8. C. Ubeda et al ., J. Clin. Invest .120, 4332 (2010).
9. N.K.Antonov et al., Antimicrob. Agents Chemother. 59,
10. B. Stecher etal .,
Proc.Natl.Acad.Sci.U.S.A. 109, 1269
11. S.Rieg et al., BMC Infect. Dis.15,475(2015).
12. A. R. Hauser, J. Mecsas, D. T. Moir, Clin. Infect. Dis. 63, 89
13. A.Zipperer et al., Nature 535,511(2016).
14. S. Caballero et al ., PLOS Pathog. 11, e1005132 (2015).
15. Evaluate Ltd, Bactroban—Worldwide Overview; http://
Our research is funded by grants from the German Center for
Infection Research to E. T., I.B. A., and A.P.; the German Research
Council to I.B.A. (SFB766 and GRK1708) and A.P. (SFB685,
TRR34, SFB766, GRK1708, and TRR156); and the European
Union to E. T. (IMI-COMBACTE-MAGNE T and DRIVE-AB) and A. P.
Formation of C–N
bonds gets an energetic
boost from photogenerated
By Travis L. Buchanan and Kami L. Hull
Amines, molecules containing carbon- nitrogen (C–N) bonds, are among the most common and biologically important molecules in organic hemistry; 84% of small-molecule pharmaceuticals contain at least one
C–N bond (1). Hydroamination, the direct
addition of an N–H bond across a carbon-carbon double or triple bond, represents an
ideal approach for the synthesis of amines
(2). Despite extensive research over the past
several decades, the efficient and direct
intermolecular hydroamination of unactivated alkenes with anti-Markovnikov regioselectivity (see the top panel of the figure)
has remained a challenge. On page 727 of
this issue, Musacchio et al. (3) report a photochemical strategy for creating reactive
ammonium radical cations (ARCs) that can
form these less stable isomers.
In pharmaceutical research, synthesis
of alkyl amines (R3C–NR2, where C is sp3-
hybridized and R is an alkyl group or hydrogen) through alkylation or reductive
amination accounts for 10.6% of reactions
performed in industrial medicinal chemistry departments (4). Although these
simple transformations are widely used,
both suffer from important limitations.
Amine alkylation reactions are often rife
with undesired side reactions, and reductive aminations typically require the use
of flammable hydride reagents (such as
Department of Chemistry, Roger Adams Laboratory, University
of Illinois, Urbana, IL 61801, USA. Email: email@example.com
“The method developed
by Musacchio et al. is
transformative in that the
is formed exclusively.”