Radiopharmaceuticals: New antimicrobial agents

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
Trends in Biotechnology (Impact Factor: 11.96). 03/2003; 21(2):70-3. 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.

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    • "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 (Figure 1). Given that microbial membranes expose negatively charged phospholipids, such as LPS or teichoic acids, on their surface, whereas mammalian cells segregate lipids with negatively charged head groups into the inner leaflet, it is conceivable that antimicrobial peptides bind preferentially to pathogens over mammalian cells [130]. "
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    ABSTRACT: Nuclear medicine imaging techniques offer whole body imaging for localization of number and site of infective foci inspite of limitation of spatial resolution. The innate human immune system contains a large member of important elements including antimicrobial peptides to combat any form of infection. However, development of antibiotics against bacteria progressed rapidly and gained popularity over antimicrobial peptides but even powerful antimicrobials failed to reduce morbidity and mortality due to emergence of mutant strains of bacteria resulting in antimicrobial resistance. Differentiation between infection and inflammation using radiolabeled compounds with nuclear medicine techniques has always been a dilemma which is still to be resolved. Starting from nonspecific tracers to specific radiolabeled tracers, the question is still unanswered. Specific radiolabeled tracers included antibiotics and antimicrobial peptides which bind directly to the bacteria for efficient localization with advanced nuclear medicine equipments. However, there are merits and demerits attributed to each. In the current paper, radiolabeled antibiotics and radiolabeled peptides for infection localization have been discussed starting with the background of primitive nonspecific tracers. Radiolabeled antimicrobial peptides have certain merits compared with labeled antibiotics which make them superior agents for localization of infective focus.
    International Journal of Peptides 05/2012; 2012(8):965238. DOI:10.1155/2012/965238
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    • "Recently, the binding of one specific (radiolabeled) synthetic fragment from UBI to various bacteria and fungi was established and enabled accumulation and visualization of experimental infections [18] [19] and the monitoring of antimicrobial therapy [14]. The observation that the synthetic fragments of UBI target to infection sites [12] opens perspectives for antimicrobial treatment with UBI derived peptides in patients [1] [13]. UBI 1–59 is of human origin and is not expected to be immunogenic for man and resistance induction is expected to be significantly lower than for classical antibiotics. "
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    ABSTRACT: The presence and antimicrobial activity of antimicrobial peptides (AMPs) has been widely recognized as an evolutionary preserved part of the innate immune system. Based on evidence in animal models and humans, AMPs are now positioned as novel anti-infective agents. The current study aimed to evaluate the potential antimicrobial activity of ubiquicidin and small synthetic fragments thereof towards methicillin resistant Staphylococcus aureus (MRSA), as a high priority target for novel antibiotics. In vitro killing of MRSA by synthetic peptides derived from the alpha-helix or beta-sheet domains of the human cationic peptide ubiquicidin (UBI 1-59), allowed selection of AMPs for possible treatment of MRSA infections. The strongest antibacterial activity was observed for the entire peptide UBI 1-59 and for synthetic fragments comprising amino acids 31-38. The availability, chemical synthesis opportunities, and size of these small peptides, combined with their strong antimicrobial activity towards MRSA make these compounds promising candidates for antimicrobial therapy and detection of infections in man.
    Peptides 12/2006; 27(11):2585-91. DOI:10.1016/j.peptides.2006.05.022 · 2.62 Impact Factor
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    ABSTRACT: 99mTc-Labeled antimicrobial peptide ubiquicidin, (99m)Tc-UBI (29-41) in a freeze-dried kit, was evaluated as a bacterial infection-seeking agent in Staphlococcus aureus- and Escherichia coli-induced infections. Thirty-three rabbits were classified in 3 groups. Biodistribution of (99m)Tc-UBI (29-41) was studied in 3 animals (group I). Uptake of peptide was determined by counting radioactivity in anatomically fitted regions drawn over the liver, kidneys, urinary bladder, and whole body and expressed as the percentage uptake per organ. Experimental thigh muscle infection was induced by injecting 2 x 10(8) colony-forming units of live S. aureus or E. coli bacteria into the right thigh muscle in 20 rabbits (group II). Turpentine oil and formalin-killed S. aureus were used for inducing sterile thigh muscle inflammation in 10 rabbits (group III). On scintigrams, anatomically adjusted regions of interest were drawn over infected/inflamed (target) and noninfected/noninflamed (nontarget) thigh, and accumulation of (99m)Tc-UBI (29-41) at sites of infection/inflammation was expressed as a target-to-nontarget (T/NT) ratio. A biodistribution study of (99m)Tc-UBI (29-41) revealed rapid removal of tracer from the circulation via the kidneys (10.6% +/- 2.1% at 5 min and 5.9% +/- 0.8% at 60 min) with accumulation of the major part in the urinary bladder within the first hour after injection (66.6% +/- 7.2%). A significantly higher (P < 0.05) accumulation of (99m)Tc-UBI (29-41) was seen at sites of S. aureus-infected animals (T/NT ratio, 2.2 +/- 0.5) compared with that of E. coli-infected animals (T/NT ratio, 1.7 +/- 0.4). The maximum tracer accumulation was observed at 60 min after injection followed by a gradual decline. No significant accumulation was noticed in thighs of rabbits injected with either turpentine oil or killed S. aureus with markedly lower T/NT ratios (P < 0.05) compared with that of S. aureus- and E. coli-infected thighs. A (99m)Tc-UBI (29-41) freeze-dried kit can be used for differentiating infections with S. aureus and E. coli with significantly higher scintigraphic intensity (P < 0.05) compared with that of sterile inflammatory sites. The optimum time for infection imaging is 60 min after injection. Relatively low (T/NT) ratios were observed in E. coli infections compared with those of the S. aureus group, which may be due to a low virulence of the former; however, other possible reasons may include low affinity of this peptide for E. coli microbial membranes.
    Journal of Nuclear Medicine 06/2004; 45(5):849-56. · 6.16 Impact Factor
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