Ionization antibacterial action

The first rigorous proof of a positive correlation between ionization and biological action was made 17 years later (Albert, Rubbo and Goldacre, 1941). This work showed that a quantitative relationship existed between antibacterial action and the percentage ionized as cations in the aminoacridine series. This correlation was then confirmed and extended (Albert etaL, 1945). 

That sulfonamides act as the anion but penetrate into the bacterial cell as the neutral species was later confirmed by comparing their behaviour in (a) a cell-free folate-synthesizing preparation of E. coli and (b) the intact cells of E. coli. The antibacterial action was directly proportional to percentage ionized in (a) but became dependent on lipophilicity, as well, in (b) (Miller, Doukos and Seydel, 1972). 

This positive correlation between ionization and bacteriostasis (illustrated in Table 2.2) was demonstrated over a wide range of bacterial species, anaerobes and aerobes, both Gram-positive and Gram-negative. Altogether over a hundred acridines were synthesized and tested, and it was always found that the substituents exerted no direct effect on the antibacterial action except in so far as they modified the ionization (Albert et al. 1945). (For more on ionization, see Chapter 10.)... 

Inhibition of polymerases. Two pieces of evidence point to the outside of the bacterial plasma membrane as the site of action of the aminoacridines. Firstly, there was no loss of antibacterial action when ionization (as cation) was increased from 70% to 100%, thus removing the more readily penetrating neutral species. Secondly, there was a great loss of activity when the aminoacridines were made more lipophilic (Albert, et al.y 1945). 

The requirement for flatness. My colleagues and I found that removal of one or two rings from 9-aminoacridine (10,15) produced molecules which had no antibacterial action, even though they remained completely ionized. This may be seen in Table lo.io by comparing 9-aminoacridine (10,15) with the structurally analogous 4-aminoquinoline (10,16) and 4-amino-pyridine (10,ly). The lack of antibacterial properties in the last two substances has been correlated with an insufficient area of flatness in these molecules (Albert, Rubbo, and Burvill, 1949). If an envelope (as shown in Fig. 10.5) is drawn around the various nuclei, an area of only 28 is obtained for quinoline and lyA for pyridine, whereas acridine has an area of 38 A ... 

First, it was shown that the bacteriostatic action of these topical antibacterials was proportional to the fraction ionized as cation (Albert, Rubbo and Goldacre, 1941). At first, it seemed puzzling that, of the five possible aminoacridines, two were highly anti-bacterial, whereas three had little activity. At that time, almost nothing was known about the ionization of heterocyclic bases, so we began to determine the values of a great many examples, and later we... 

An ideal antimicrobial agent should be non-toxic and possess broad-spectrum antiviral, antibacterial, and antifungal activity and exclude resistance. This has led to the design of a combination agent, iodine-lithium-alpha-dextran [66 ]. This uses the non-specific antimicrobial action of molecular and ionized iodine and the systemic immunomodulatory effects of the polysaccharide complex of iodine and lithium. This new agent has been assessed by parenteral administration in HIV-infected patients. The adverse effects of phlebitis of punctured small veins and subfebrile fever,... 

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