Antibiotic carriers

The crowns as model carriers. Many studies involving crown ethers and related ligands have been performed which mimic the ion-transport behaviour of the natural antibiotic carriers (Lamb, Izatt Christensen, 1981). This is not surprising, since clearly the alkali metal chemistry of the cyclic antibiotic molecules parallels in many respects that of the crown ethers towards these metals. As discussed in Chapter 4, complexation of an ion such as sodium or potassium with a crown polyether results in an increase in its lipophilicity (and a concomitant increase in its solubility in non-polar organic solvents). However, even though a ring such as 18-crown-6 binds potassium selectively, this crown is expected to be a less effective ionophore for potassium than the natural systems since the two sides of the crown complex are not as well-protected from the hydro-phobic environment existing in the membrane. 

Facilitated diffusion (i.e./ via antibiotic carriers or membrane channels). 

Hyaluronan microparticles [209] Sulfadiazine Microparticle Local antibiotic carrier... 

If a more elective result is sought for by associating the pump with another valve membrane, one can propose [114-115] to take advantage of the recent lipid membranes containing antibiotics through which only the cations complexed by the antibiotic-carrier can pass. If valinomycin is used only will pass and not Na" one K for each split ATP . 

In essence, the cephalosporin acts as a carrier (63) for the quinolone. The quinolone is replaced in the bacterial ceU after the action of P-lactamase on the cephalosporin portion of the molecule. This codmg combination represents a relatively new class of antibacterial agents which appear to offer advantages over the separated components (64). A good introductory discussion of these exciting agents can be found (65) (see also Antibiotics P-lactams ... 

A second source of inspiration for studying the open-chained equivalents of crown ethers was the observation that a number of naturally occurring antibiotics enhance cation transport and bear a structural similarity to open-chained crown ethers. A number of groups have examined neutral synthetic ionophores and a variety of novel cation carriers is now available. This is discussed in Sect. 7.4, below. 

All of the transport systems examined thus far are relatively large proteins. Several small molecule toxins produced by microorganisms facilitate ion transport across membranes. Due to their relative simplicity, these molecules, the lonophore antibiotics, represent paradigms of the mobile carrier and pore or charmel models for membrane transport. Mobile carriers are molecules that form complexes with particular ions and diffuse freely across a lipid membrane (Figure 10.38). Pores or channels, on the other hand, adopt a fixed orientation in a membrane, creating a hole that permits the transmembrane movement of ions. These pores or channels may be formed from monomeric or (more often) multimeric structures in the membrane. 

As carriers of antibiotic resistance (Chapter 3, Part 4) the emergence of antibiotic-resistant strains has had serious repercussions in the application of antibiotic therapy, and has seriously increased the danger of nosicomial infections. 

Rasor and Tischer (1998) have brought out the advantages of enzyme immobilization. Examples of penicillin-G to 6-APA, hydrolysis of cephalospwrin C into 7-ACA, hydrolysis of isosorbide diacetate and hydrolysis of 5-(4-hydroxy phenyl) hydantom are cited. De Vroom (1998) has reported covalent attachment of penicillin acylase (EC 3.51.11) from E.Coli in a gelatine-based carrier to give a water insoluble catalyst assemblase which can be recycled many times, and is suitable for the production of semi-synthetic antibiotics in an aqueous environment. The enzyme can be applied both in a hydrolytic fashion and a synthetic fashion. 6-APA was produced from penicillin-G similarly, 7-ADCA was produced from desa acetoxycephalosporin G, a ring expansion product of penicillin G. 

Neutral carriers are organic complexing agents which are capable of sequestering and transporting ionic species in a hydrophobic organic phase. The antibiotics, valino-mycin and nonactin were the first neutral carriers to be incorporated in an ISE These macrocyclic neutral carriers contain a polar internal cavity and an outer hydro-phobic shell. The excellent selectivity exhibited by valinomycin for potassium ions is... 

A number of substances have been discovered in the last thirty years with a macrocyclic structure (i.e. with ten or more ring members), polar ring interior and non-polar exterior. These substances form complexes with univalent (sometimes divalent) cations, especially with alkali metal ions, with a stability that is very dependent on the individual ionic sort. They mediate transport of ions through the lipid membranes of cells and cell organelles, whence the origin of the term ion-carrier (ionophore). They ion-specifically uncouple oxidative phosphorylation in mitochondria, which led to their discovery in the 1950s. This property is also connected with their antibiotic action. Furthermore, they produce a membrane potential on both thin lipid and thick membranes. 

It is now recognised that a wide range of organic molecules, collectively termed ionophores 185,186) or complexones 187), are able to facilitate ion (usually cation) transport. Two major mechanisms have been revealed for this process, namely the involvement of transmembrane ion carriers and transmembrane pores or channels (see Fig. 19). The majority of ionophores studied to date are natural antibiotics and their synthetic analogues which are, on a biological scale, comparatively small molecules lending themselves to study outside the biological system. In contrast far less is known about the molecular structures involved in normal transport processes. Such molecules are likely to be more complex or present in small amounts and may require... 

PJ Sinko, GL Amidon. Characterization of the oral absorption of P-lactam antibiotics. II. Competitive absorption and peptide carrier specificity. J Pharm Sci 78 723-727, 1989. 

Ishizawa, T., et al. Sodium and pH dependent carrier-mediated transport of antibiotic, fosfomydn, in the rat intestinal brush-border membrane. J. Pharmacobiodyn. 1990, 13, 292—300. 

Cefadroxyl and cefaclor are beta-lactam antibiotics which show high affinity for the PepTl carrier system, whereas the other two beta-lactams, cephalotin and cef-metazole, are not recognized by PepTl protein and are not actively transported in the intestine. However, as the VolSurf Caco-2 model predicts that all the beta-lactams are nonpenetrating compounds, it is very probable that, as they rely only the diffusion mechanism, cefadroxyl and cefaclor will not cross the cell monolayer. 

There appear to be two major ways by which ionophores aid ions to cross membrane barriers. Ionophores such as valinomycin and nonactin enclose the cation such that the outside of the complex is quite hydro-phobic (and thus lipid-soluble). The transport behaviour thus involves binding of the cation at the membrane surface by the antibiotic, followed by diffusion of the complexed cation across the membrane to the opposite surface where it is released. Such carrier type ionophores can be very efficient, with one molecule facilitating the passage of thousands of ions per second. A prerequisite for efficient transport by this type of ionophore is that both the kinetics of complex formation and dissociation be fast. 

There are various pathways for free radical-mediated processes in microsomes. Microsomes can stimulate free radical oxidation of various substrates through the formation of superoxide and hydroxyl radicals (the latter in the presence of iron) or by the direct interaction of chain electron carriers with these compounds. One-electron reduction of numerous electron acceptors has been extensively studied in connection with the conversion of quinone drugs and xenobiotics in microsomes into reactive semiquinones, capable of inducing damaging effects in humans. (In 1980s, the microsomal reduction of anticancer anthracycline antibiotics and related compounds were studied in detail due to possible mechanism of their cardiotoxic activity and was discussed by us earlier [37], It has been shown that semiquinones of... 

Antibiotics shorten the duration of diarrhea, decrease the volume of fluid lost, and shorten the duration of the carrier state (see Table 39-3). A single dose of oral doxycycline is the preferred agent. In children younger than 7 years of age, trimethoprim-sulfamethoxazole, erythromycin, and furazolidone can be used. In areas of high tetracycline resistance, fluoroquinolones are effective. 

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