The effects of chlorpromazine on the outer cell wall of Salmonella typhimurium in ensuring resistance to the drug

Chlorpromazine (CPZ), a compound employed for the management of psychosis, has a wide ranging antibacterial activity. The growth of Salmonella typhimu rium, while highly resistant to CPZ (MIC > 100 mg/l): was initially inhibit ed during the first 8-16 h of exposure to concentrations of CPZ below the M IG. During this period of transient susceptibility, the distribution of rib osomes was markedly altered in a concentration dependent manner; the rough cell wall was transformed into a smooth form. The protein composition of th e outer cell wall of 55 kDa was markedly decreased, whilst there was an inc reased number of high molecular weight proteins. After 16 h of exposure to sub-MIG levels of CPZ, the inhibitory effect of the drug was no longer appa rent whereas the effects noted on the cell wall were retained. These Salmon ella were: as the control, agglutinated by O antigen specific antibody. Whe reas agglutination of the control Salmonella was blocked by the presence of CPZ at concentrations that induced the cell-wall effects, agglutination of CPZ exposed-Salmonella for periods in excess of 16 h was not blocked by an y concentration of CPZ. These results suggested that eventual resistance to CPZ was dependent upon changes induced by CPZ at the cell wall level. The results also suggested that the CPZ binds to the 55 kDa protein and that su ch binding interfered with the recognition of the O antigen by antibody. (C ) 2000 Elsevier Science B.V, and International Society of Chemotherapy. All rights reserved.