Radiopharmaceuticals: New antimicrobial agents

Article (PDF Available)inTrends in Biotechnology 21(2):70-3 · March 2003with67 Reads
DOI: 10.1016/S0167-7799(02)00032-X · Source: PubMed
Small antimicrobial peptides are good candidates for new antimicrobial agents. A scintigraphic approach to studying the pharmacokinetics of antimicrobial peptides in animals has been developed. The peptides were safely and reproducibly labelled with technetium-99m and, after intravenous injection of the radiolabelled peptides into infected animals, scintigraphy allowed real-time quantification of the peptide in the various body compartments. Antimicrobial peptides rapidly accumulated at sites of infection but not at sites of sterile inflammation, indicating that radiolabelled antimicrobial peptides could be used in detection of infection. These radiopharmaceuticals enabled the efficacy of antibacterial therapy in animals to be monitored. The scintigraphic approach provides a useful method for investigating the pharmacokinetics of small peptides in animals.


Radiopharmaceuticals: new
antimicrobial agents
Antonella Lupetti
, Peter H. Nibbering
, Mick M. Welling
and Ernest K.J. Pauwels
Dept of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
Dipartimento di Patologia Sperimentale, Biotecnologie Mediche, Infettivologia ed Epidemiologia, Universita` degli Studi di Pisa,
Pisa, Italy
Dept of Radiology, Division of Nuclear Medicine, C4-Q, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden,
The Netherlands
Small antimicrobial peptides are good candidates for
new antimicrobial agents. A scintigraphic approach to
studying the pharmacokinetics of antimicrobial pep-
tides in animals has been developed. The peptides were
safely and reproducibly labelled with technetium-99m
and, after intravenous injection of the radiolabelled pep-
tides into infected animals, scintigraphy allowed real-
time quantification of the peptide in the various body
compartments. Antimicrobial peptides rapidly accumu-
lated at sites of infection but not at sites of sterile
inflammation, indicating that radiolabelled antimicrobial
peptides could be used in detection of infection. These
radiopharmaceuticals enabled the efficacy of antibacter-
ial therapy in animals to be monitored. The scintigraphic
approach provides a useful method for investigating
the pharmacokinetics of small peptides in animals.
Antimicrobial peptides, produced by phagocytes, epithelial
cells, endothelial cells and many other cell types, are an
important component of innate immunity against infec-
tion by a variety of pathogens [14]. They can be expressed
constitutively or induced during inflammation or microbial
challenge. The main features of antimicrobial peptides are
described in Box 1, and an online catalogue of all reported
molecules can be consulted at http://www.bbcm.univ.trieste.
it/~tossi/antimic.html. Antimicrobial peptides display anti-
bacterial, antiviral and antifungal activities in vitro [510]
and are effective in experimental infections with multi-
drug resistant Staphylococcus aureus [11] and Mycobac-
terium tuberculosis [12]. Interestingly, the antibacterial
effect of antimicrobial peptides in experimentally infected
animals might also be attributed to synergistic effects with
endogenous antimicrobial peptides and proteins (such as
lysozyme and secretory leukoprotease inhibitor (SLPI)
[13]), reactive oxygen intermediates [14], or other local
factors (such as pH, Ca
and Zn
concentrations) or to
interactions with host cells, leading to enhanced anti-
bacterial activities of the cells. In view of the emergence of
pathogens with increased resistance to conventional anti-
infectives, the use of antimicrobial peptides alone or in
combination with current antifungal drugs could lead to
the development of new therapies to combat otherwise
resistant infections [15].
Inserting the peptides into the bacterial cytoplasmic
membrane under the influence of the transmembrane
electrical potential gradient results in transient per-
meability of membranes and leakage of cellular constitu-
ents, such as potassium ions, thus destroying the proton
gradient across the membrane [2] and resulting in
bacterial cell death. Although membrane permeabilisation
is an essential step in cell death, several lines of evidence
indicate that, in the process of killing Candida, some
antimicrobial peptides (i.e. histatin- and lactoferrin-
derived peptides) have an effect on membranes through
an action on the energized mitochondrion [10,1618].
Although antimicrobial peptides have different chemical
structures, the basis of their antimicrobial activities is the
interaction of the cationic (positively charged) domains of
the peptides with the (negatively charged) surface of
microorganisms (Fig. 1) [3]. Given that microbial mem-
branes expose negatively charged phospholipids, such as
lipopolysaccharide (LPS) or teichoic acids, on their surface,
whereas mammalian cells segregate lipids with negatively
charged headgroups into the inner leaflet, it is conceivable
Fig. 1. The membrane target of antimicrobial peptides and the basis of their
specific binding. Adapted, with permission, from [3].
TRENDS in Biotechnology
Acidic phospholipids
Zwitterionic phospholipids
Bacterial cytoplasmic membrane
Prototype plasma membrane of a
multicellular animal (erythrocyte)
Inner leaflet
Outer leaflet
Weak Strong
Hydrophobic interactions Electrostatic and
hydrophobic interactions
Antimicrobial peptide
Corresponding author: Ernest K.J. Pauwels (
Opinion TRENDS in Biotechnology Vol.21 No.2 February 2003
70 0167-7799/03/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved. PII: S0167-7799(02)00032-X
that antimicrobial peptides bind preferentially to patho-
gens over mammalian cells.
Large-scale production of antimicrobial peptides
Large quantities of purified microbial peptides are
required to investigate their possible applications further.
Difficulties arising in purifying natural antimicrobial
peptides from various sources have prompted the recom-
binant production of antimicrobial peptides by genetically
engineered bacteria [19,20] or by peptide synthesis [21,22].
Such methods result in sufficient amounts of antimicrobial
peptides produced under good laboratory practice con-
ditions, which is essential for future approval to use the
peptides in clinical trials. Peptide synthesis also allows the
production of chemical variants, such as
peptides that have amino acid substitutions at various
positions, and peptide libraries. Furthermore, synthetic
peptides are usually small, rapidly removed from the
circulation and other body compartments, and flexible,
because they do not hold a particular structure in a
hydrophilic environment, and they display a favourable
adverse effect profile. Alternatively, yeast recombinant
technology can be used for large-scale production of
cysteine-rich peptides that have several disulfide bridges,
which make them naturally very resistant to protease
degradation because of their compact structure. It is our
belief that both synthetic and recombinant antimicrobial
peptides are the candidates of choice for further develop-
ment as antimicrobial agents.
Measuring the pharmacokinetics of antimicrobial
The classic method for studying the pharmacokinetics of
small peptides in animals is to measure their levels in
different organs at various intervals after injection using
biochemical (or immunological) assays. A major disadvan-
tage of this approach is that it does not allow whole-body,
real-time monitoring of the biodistribution of the peptide
in an individual animal. To circumvent this drawback,
peptides need to be labelled to assess the biodistribution of
the labelled peptides in animals. In the case of small
peptides, it is not feasible to analyse their pharmacoki-
netics by preparing a fusion protein of the peptide under
study with, for example, green fluorescent protein or
luciferase, both of which can be monitored in animals in
real-time [23,24]. Alternatively, peptides can be tagged
with radioisotopes, such as technetium-99m (
indium-111 and iodine-125, and scintigraphic techniques
can be used to quantify the amount of radiolabelled
peptides in different organs at various intervals. Because
of its favourable radiation characteristics and ready
Tc is the preferred label for studying the
pharmacokinetics of peptides.
Radiolabelling of peptides
The aim of radiolabelling techniques is to firmly attach or
incorporate the radionuclide into the peptide without
altering its biological functions, thus allowing a reliable
evaluation of its pharmacokinetics after intravenous
administration. The various methods of labelling peptides
Tc, including indirect labelling using the pre-
formed chelate approach or bifunctional chelating agents,
and the direct labelling method have been discussed
extensively [25,26]. The direct labelling method is a simple
procedure in which the peptide is labelled in absence of an
exogenous chelator. Using such a technique [27] and the
Tc, an array of peptides was labelled
including those with disulfide bridges without affecting
Box 1. Key features of antimicrobial peptides
Antimicrobial peptides usually contain , 50 amino acids with a net
positive charge created by an excess of basic residues, such as lysine
and arginine, and , 50% hydrophobic amino acids.
Antimicrobial peptides are essential components of the innate host
defence because of their ability to kill a wide range of pathogens.
They have a wide distribution throughout the animal and plant
They are effectors of local and systemic immune responses. The latter
is essentially found in insects [a].
Although they share basic features such as small size, hydrophobicity
and cationic character, antimicrobial peptides have a great structural
diversity. For the sake of simplicity they can be categorized into three
main families:
linear peptides that adopt an amphipathic a-helical structure
such as cecropin, magainins, bee mellitin and human
ubiquicidin and histatins;
peptides with disulde bridges (1 to 4) that may adopt a loop
or a b-sheet structure. Interestingly, the core of some 3-
disulde bonded peptides, such as plant and insect
defensins, combines a-helical regions and b-sheet struc-
tures connected by two of the three disulde bridges,
forming a cysteine-stabilized a/b motif;
peptides that are particularly rich in one amino acid (beside
lysine and arginine) such as the tryptophan-rich indolicidin
of bovine neutrophils and the proline-arginine-rich peptide
PR39 of pig neutrophils.
The majority of antimicrobial peptides are derived from larger
precursors that harbor a signal sequence, whereas other peptides are
generated by proteolysis from larger proteins (such as lactoferricin).
In addition, some antimicrobial peptides such as mammalian
defensins and LL-37 have other activities contributing to host
defences by mediating an acute inammatory reaction [b,c] and
linking the innate with the acquired immune response [d,e].
a Lemaitre, B. et al. (1997) Drosophila host defense: differential
induction of antimicrobial peptide genes after infection by various
classes of microorganisms. Proc. Natl Acad. Sci. U.S.A. 94,
b Welling, M.M. et al. (1998) Antibacterial activity of human
neutrophil defensins in experimental infections in mice is
accompanied by increased leukocyte accumulation. J. Clin. Invest.
102, 1583 1590
c Niyonsaba, F. et al. (2001) Evaluation of the effects of peptide
antibiotics human b-defensins-1/-2 and LL-37 on histamine release
and prostaglandin D(2) production from mast cells. Eur. J. Immunol.
31, 1066 1075
dYang, al. (1999) b-Defensins: linking innate and adaptive
immunity through dendritic and T cell CCR6. Science 286,
e Biragyn, A. et al. (2002) Toll-like receptor 4-dependent activation of
dendritic cells by b-defensin 2. Science 298, 1025 1029
Opinion TRENDS in Biotechnology Vol.21 No.2 February 2003
their biological functions [5]. In addition, radiochemical
analysis showed that the labelling of antimicrobial
peptides was rapid (within 10 min), effective (impurities
, 5% of the total radioactivity), stable (minimal release of
radioactivity from the
Tc-peptide in diluted human
serum) and safe (no adverse effects in mice and rabbits).
Unfortunately, the reaction mechanism underlying this
Tc-labelling of peptides has not been elucidated. It may,
however, involve the reduction of technetium, the pro-
duction of a technetium intermediate, and the substitution
reaction transferring the reduced technetium from this
intermediate to the peptide. The end-product from this
reaction could be a reduced metal(N4) complex, as reported
formanytetrapeptides [28].Frompreliminarydata obtained
using reverse-phase high-performance liquid chromato-
graphy (HPLC), it seems that this complex probably
contains two peptide molecules around a reduced Tc core.
Application of labelled peptides for infection detection
Scintigraphic studies after intravenous injection of non-
microbicidal concentrations of radiolabelled antimicrobial
peptides into animals revealed that the peptides are
rapidly cleared from the circulation (half-life 30 60 min)
via the kidneys and bladder with little activity in the liver
and no deposits in the intestines. Moreover, this favour-
able kinetic prole is accompanied by a limited radiation
burden. An example of the scintigraphic data obtained
with a
Tc-labelled synthetic peptide corresponding to
residues 2941 of the antimicrobial peptide ubiquicidin
(UBI 29 41) in a rabbit is shown in Figure 2a.
These studies also triggered the idea that this labelling
technique could be useful for other applications, such as
infection detection. Although most infections are diag-
nosed on the basis of clinical history, physical examination,
medical imaging and identication of pathogens in body
uids and biopsies, in a select group of patients (transplant
recipients and patients with prosthesis), fever could be
owing to both infectious and inammatory processes, such
as allograft rejection. In such patients, radiopharma-
ceuticals that discriminate infections from sterile inam-
mations can therefore make an important contribution to
the non-invasive diagnosis of infections by means of
scintigraphy. Selected radiolabelled antimicrobial pep-
tides accumulated rapidly (within 30 min) in the target
(infected) tissues (12% of the injected dose) with little
accumulation at sites of sterile inammation, allowing
bacterial and fungal infections to be distinguished from
sterile inammation [29,30]. An example of the uptake
characteristics of
Tc-labelled antimicrobial peptides in
infected or inamed thigh muscles in rabbits is given in
Figures 2b and 2c, respectively. In agreement with the
specicity of the in vitro binding of antimicrobial peptides
to microorganisms, in vivo competition studies using
unlabelled peptides as competitors indicated that, in
addition to charge, the composition and sequence of peptides
are key to their abilityto accumulate at sites of infection [31].
For example, accumulation of
Tc-labelled UBI 2941
at the site of infection in mice could be inhibited by
injecting an excess of the unlabelled UBI 2941, but not by
a scrambled version of this peptide, before injection of the
tracer [31]. Interestingly, various
Tc-labelled UBI
peptides can be useful in infection detection in both
immunocompetent and immunocompromised animals.
Furthermore, a good correlation between the accumu-
lation of
Tc-labelled UBI2941 peptides in bacterial
infected thigh muscles of mice and the number of viable
microorganisms present at the site of infection was found,
indicating that our approach using radiolabelled peptides
could be applied to monitor the efcacy of antimicrobial
therapy of bacterial infections.
Scintigraphic analysis of
Tc-labelled peptides after
intravenous injection is the method of choice for studying
the pharmacokinetics of small antimicrobial peptides in
animals because it allows reliable real-time, whole-body
imaging and quantitative biodistribution studies without
the need to kill animals at each interval. Using this
Fig. 2. (a) Biodistribution of
Tc-labelled UBI 29 41 in a healthy rabbit 2 h after intravenous injection of the radiolabelled peptide. In short,
Tc-UBI 2941 injected into a
normal rabbit was rapidly cleared from the circulation (half-life , 3060 min) via the kidneys and bladder, with little activity in the liver and no deposits in the intestines.
(b) Typical scintigram of
Tc-labelled UBI 2941 2 h after injection of the tracer into rabbits that had been infected intramuscularly with 10
colony forming units multi-
drug resistant Staphylococcus aureus or (c) injected with a 20-fold higher number of heat-killed multidrug resistant S. aureus. To determine whether the labelled peptide
specically accumulated at the site of infection or inammation we calculated the ratio between the radioactivity in the affected and the contralateral thigh muscle. The
ratios seen in infected animals, but not inamed, were signicantly higher than in normal rabbits. The infected or inamed thigh muscle is indicated by an arrow. Adapted,
with permission, from [29].
Opinion TRENDS in Biotechnology Vol.21 No.2 February 2003
approach, quantitative data can be obtained within
seconds after injection of the radiolabelled peptide up to
, 12 h and the labelling procedure does not alter the
biological functions of antimicrobial peptides [5].In
addition, our scintigraphic approach allows the analysis
of the pharmacokinetics of not only peptides but also a
wide range of probes, including anti-infectives [29,32,33],
large proteins [34] and even cells [35]. For example,
comparing the pharmacokinetics of
Tc-labelled natu-
ral and transgenic human lactoferrin in mice indicated
similar half-lives and both proteins were excreted by the
liver, intestines, kidneys and bladder [34]. These results
were in agreement with data for the transgenic human
lactoferrin obtained in human volunteers.
As a spin-off from our research, we found that
radiolabelled antimicrobial peptides can be useful in
infection detection and monitoring of the efcacy of
antibacterial therapy in animals. Currently, we are
focusing on the discrimination between infection and
sterile inammation in (immunocompromised) animals
that have an articial implant, for example a prosthetic
knee, hip or heart valve, using radiolabelled peptides.
Clearly, more information, such as knowledge of
the molecular structure and the toxicology of the
Tc-labelled end-product, is required before considering
the use of
Tc-labelled peptides for detection of infec-
tious processes in humans.
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Opinion TRENDS in Biotechnology Vol.21 No.2 February 2003
    • "The compound should also have low toxicity and not induce an immune response. Very importantly, it should be able to distinguish between a sterile and an infected inflammation [45]. Since antimicrobial peptides generally show a broad spectrum of activity against a wide range of pathogenic yeasts and bacteria they are ideal targeting molecules for infections where the suspected pathogen has not been identified . "
    [Show abstract] [Hide abstract] ABSTRACT: Antimicrobial peptides (AMPs) are a heterogeneous class of compounds found in a variety of organisms including humans and, so far, hundreds of these structures have been isolated and characterised. They can be described as natural microbicide, selectively cytotoxic to bacteria, whilst showing minimal cytotoxicity towards the mammalian cells of the host organism. They act by their relatively strong electrostatic attraction to the negatively charged bacterial cells and a relatively weak interaction to the eukaryote host cells. The ability of these peptides to accumulate at sites of infection combined with the minimal host's cytotoxicity motivated for this review to highlight the role and the usefulness of AMPs for PET with emphasis on their mechanism of action and the different interactions with the bacterial cell. These details are key information for their selective properties. We also describe the strategy, design, and utilization of these peptides as potential radiopharmaceuticals as their combination with nuclear medicine modalities such as SPECT or PET would allow noninvasive whole-body examination for detection of occult infection causing, for example, fever of unknown origin.
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    • "Tracers that can diagnose specific infectious processes and monitor effectiveness of (antimicrobial or anti-inflammatory) therapy are therefore of great promise. During the last decade, various research groups studied the potency of imaging and treatment of drug-resistant pathogens using radiolabeled antimicrobial compounds [24], and the radiopharmacy and pharmacology of cationic AMPs are well established [25]. Examples of radiolabeled natural AMPs, which have been intensively evaluated for the imaging of infections in animal models, are (recombinant) lactoferrins, defensins, histatins, and ubiquicidin [23,38,39]. "
    [Show abstract] [Hide abstract] ABSTRACT: Cerebral aggregation of amyloid-β (Aβ) is thought to play a major role in the etiology of Alzheimer's disease. Environmental influences, including chronic bacterial or viral infections, are thought to alter the permeability of the blood-brain barrier (BBB) and thereby facilitate cerebral colonization by opportunistic pathogens. This may eventually trigger Aβ overproduction and aggregation. Host biomolecules that target and combat these pathogens, for instance, antimicrobial peptides (AMPs) such as Aβ itself, are an interesting option for the detection and diagnostic follow-up of such cerebral infections. As part of the innate immune system, AMPs are defensive peptides that efficiently penetrate infected cells and tissues beyond many endothelial barriers, most linings, including the BBB, and overall specifically target pathogens. Based on existing literature, we postulate a role for labeled AMPs as a marker to target pathogens that play a role in the aggregation of amyloid in the brain.
    Full-text · Article · Mar 2014
    • "The direct labeling method is a simple procedure in which the peptide is labeled in absence of an exogenous chelator (Lupetti et al., 2003b). The direct approach is characterized by poorly defined chemical structures, and it is generally thought that the 99mTc binds to the sulfhydryl groups produced by reduction of the peptide disulfide bridge. "
    [Show abstract] [Hide abstract] ABSTRACT: Despite the advances in public health during the 18th and 19th centuries and the introduction of immunization and antibiotics in the 20th century, bacterial infection is among the most frequently encountered and costly causes of diseases and one of the major causes of morbidity and mortality especially in developing countries (El-Ghany et al., 2005). Localizing and distinguishing the “infection foci” in body sites are very important and life saving processes. The identification of an infection at early stage of disease is critical for a favorable outcome. The diagnosis of deep seated infections such as osteomyelitis, endocarditis and intra- abdominal abscesses is still a challenging problem. Although imaging techniques such as x-ray, computerized tomography (CT-scan), magnetic resonance imaging (MRI) and ultrasonography (US) might be helpful, but none of these techniques are specific for infection diagnosis because of their limitations due to insignificant anatomical changes in the early stages of the infection process. In addition, these techniques are not capable of differentiating between inflammatory and infectious processes. In contrast, nuclear medicine procedures can determine the location and the degree of disease activity in infectious processes based on physiologic and/or metabolic changes that are associated with these diseases rather than gross changes in the structure (Hall et al., 1998). This method requires a reliable radiopharmaceutical that can selectively concentrate in sites of infection. Various 99mTc-labeled compounds have been developed for the scintigraphic detection of infection and sterile inflammation in humans. Unfortunately, these radiopharmaceuticals do not discriminate between infection and sterile inflammatory process, which is often of clinical importance (Welling et al., 2001). In recent years, the development of radiolabeled antimicrobial agents for specific diagnosis of infection has received considerable attention, sparking a lively debate about the infection specificity of these radiopharmaceuticals (Oyen et al., 2005). Direct targeting of the locally present microorganisms is a new approach for improving the selectivity of radiopharmaceuticals for infection detection in nuclear medicine (Kyprianidou et al., 2011). The use of radiolabeled antibiotics and antimicrobial peptides are fast emerging as promising targeted diagnostic tests for detection of infective lesions because of their specific binding to the bacterial component. These targeting molecules reliably locate sites of infection and make a differential diagnosis between infection and sterile inflammation. In this chapter, the new approaches to scintigraphic imaging of infection and inflammation by radiolabeled antibiotics and antimicrobial peptides are thoroughly discussed in order to assess their diagnostic value as targeting imaging radiopharmaceuticals.
    Full-text · Chapter · Feb 2013 · Alzheimer's & dementia: the journal of the Alzheimer's Association
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