Fundamentals of Medicinal Chemistry

C-Terminus Two N-Termini

Ions

Channel C-Terminus

(a) (b)

(HOOC)Val−Gly−Ala−Leu−Ala−Val−Val−Val−Trp−Leu

HOCH 2 CH 2 NHTrp−Leu−Trp−Leu−Trp

D

L D L D L

L L D L D L D L

(Configurations)

3

HN

CH

H 3 CCH 3

COO

CH 3

CONH

CH

H 3 C CH 3

C COO CH

H

C

H

C

H

H

CO

CH

CH CH^3

3

D-Valine L-Lactic L-Valine

acid

D-Hydroxy

isovaleric acid

Figure 7.1 The general mode of action of ionophores in ion transport. (a) A channel formed by

two gramicidin A molecules, N-terminus to N-terminus. (b) The sequence of events in the

operation of a carrier ionophore such as valinomycin. Valinomycin is a cyclic peptide consisting

of three repeating units with the structure shown

7. 2. 2. 2 Cell wall synthesis inhibition

The cell walls (Appendix 3) of all bacteria are being continuously replaced

because they are continuously being broken down by enzymes in the extracellu-

lar fluid. Antibacterial agents, commonly referred to as antibiotics, often act by

inhibiting this replacement biosynthesis of the cell wall at any stage in its

formation. Most drugs that act in this fashion inhibit either the formation of

the precursor starting compounds, the formation of the peptidoglycan chains or

the cross linking of the peptidoglycan (Table 7.2). However, increasing numbers

of bacteria are resistant to antibiotics, especially tob-lactam antibiotics. This

resistance is likely to become a major problem in the future.

The activity of the penicillins and cephalosporins is believed to be due to the

b-lactam ring. Bacterial resistance to these drugs is thought to be mainly due to

inactivation of the drug by hydrolysis of theb-lactam ring by theb-lactamases

produced by the bacteria. Both Gram-positive and Gram-negative bacteria

(Appendix 2) produceb-lactamases. In the former case, the enzyme is liberated

into the medium surrounding the the bacteria, which results in the hydrolysis of

136 SELECTED EXAMPLES OF DRUG ACTION AT SOME COMMON TARGET AREAS