Antimycobacterial Calixarenes Enhance Innate Defense Mechanisms in Murine Macrophages and Induce Control ofMycobacterium tuberculosisInfection in Mice

Abstract

Tuberculosis remains the leading cause of death among infectious diseases, accounting for more than two million deaths annually. The incidence of the disease is increasing globally, partially because of the resurgence of drug-resistant strains of Mycobacterium tuberculosis. Calixarenes are macrocyclic oligomers, some of which are able to modify the growth of M. tuberculosis in infected cells. Most experimental work has been carried out with Macrocyclon, also known as HOC 12.5EO. In this study, we demonstrate that Macrocyclon is effective in controlling M. tuberculosis infections, and we provide evidence that its effect is partially mediated by an L-arginine-dependent mechanism of macrophage activation that involves the activity of the inducible nitric oxide synthase. We also show that Macrocyclon is effective in athymic and major histocompatibility complex class II ؊/؊ mice and synthesized a number of structurally related calixarenes expressing significant antimycobacterial activity.Mycobacterium tuberculosis infects one-third of the world's population, and it accounts for more deaths each year than any other infectious bacterium (13). The problem, associated with multiple-drug resistance (12), has prompted a great interest in understanding new alternatives in host-mediated mechanisms of disease intervention. A new therapeutic agent, with activity mediated through a host-derived effector mechanism, would be particularly attractive, since it could be less susceptible to selection for drug resistance; if the balance between the pathogenic mycobacteria and the macrophage can be manipulated in favor of the host macrophage, it may be possible to develop novel adjunctive therapies for tuberculosis control.Calixarenes have been used as building blocks for host molecules with numerous applications in supramolecular chemistry (5); some were identified as having antimycobacterial activity (3, 7). Most experimental work has been carried out with the compound Macrocyclon, also known as HOC 12.5EO, which was prepared by reacting the macrocycle HOC under basic conditions with ethylene oxide to give a heterogeneous compound with an average polyethylene glycol (PEG) chain of 12.5 U (3). The compound HOC was prepared from t-octylphenol and formaldehyde by a modified Zinke-Ziegler procedure; for many years, it was believed to be a cyclic tetrameric compound (3). Although the antibacterial mechanism of action of HOC compounds is not known, we have excluded extracellular inhibition of mycobacterial growth by Macrocyclon treatment (3,7,8). Therefore, it is believed that they work through a host-mediated mechanism (7), a view supported by reports showing activity in a wide range of in vivo models of infection in addition to tuberculosis (10). In this study, we have extended observations on the parent preparation, Macrocyclon, to show that it significantly affects mycobacterial growth in murine macrophages by a mechanism requiring inducible nitric oxide synthase (iNOS) activity. In addition, we show that Macrocyclon is effective in at...

Moulding calixarenes for biomacromolecule targeting

“…The proximity of these quite different ligating units, reinforces the binding within supramolecular partners by exploiting synergistic and solvation-desolvation effects. 31 The binding mode shown by the Vancomycin mimic calixarene ligands, able to address a single amino acid (or a very limited number of amino acids) in a large biopolymer could be systematically classified as "single point" recognition ( Figure 5b), a way of binding very recently elegantly exploited by Crowley and Hof to recognize a protein mutated on single positions upon methylation of the Lysine residues (vide infra). Vancomycin is, in fact, a natural antibiotic whose activity is linked to its ability to selectively recognize the terminal L-Lys-D-Ala-D-Ala sequence of peptidoglycan, one of the main cell wall constituents in Gram-positive bacteria.…”

Applications of calixarene nano-baskets in pharmacology

“…Calixarenes are able to modify its growth and macrocyclon is effective in controlling its infections. Colston et al [42] revealed that macrocyclons (Fig. 5) were effective in athymic and they synthesized a number of structurally related calixarenes expressing significant antimycobacterial activity.…”

Antimicrobial Activity of Calixarenes and Related Macrocycles

“…In a later paper, D'Arcy Hart and colleagues revisited these compounds and compared Macrocyclon, with an average of 12.5 -CH 2 CH 2 O-repeat units and terminating in a hydroxy group, with 'HOC-60', 67, an analogue with 60 repeat units [47]. At this point, it was also appreciated that the compounds were calix[8]rather than calix [4] [48]. In these later experiments, both macrophages and live mice were infected with M. tuberculosis and the range of calixarenes, 68 to 72 (Figure 13), increased.…”