Obligate intracellular bacteria and antibiotic resistance

Abstract

First, these bacteria could be incapable of easily acquiring new genes, including resistance genes. Of the obligate intracellular Gram-negative bacteria, only Coxiella burnettii has been shown to be capable of carrying plasmids. These plasmids can vary in size and possible functions in strains derived from different clinical forms of related diseases, but their exact purpose remains unknown19xMechanisms that may account for differential antibiotic susceptibilities among Coxiella burnetii isolates. Yeaman, M.R. and Baca, O.G. Antimicrob. Agents Chemother. 1991; 35: 948–954Crossref | PubMedSee all References19. Chlamydia spp. and the intracytoplasmic bacteria Rickettsia spp. and Lawsonia sp. have shown no evidence of possessing functional plasmids. The various antibiotic-resistance genes carried on plasmids could therefore be unavailable to these bacteria. By contrast, Listeria spp. capable of retaining plasmids in an intracellular habitat also exhibit both tetracycline- and macrolide-resistance genes20xAntibiotic resistance in Listeria spp. Charpentier, E. and Courvalin, P. Antimicrob. Agents Chemother. 1999; 43: 2103–2108PubMedSee all References20. The intracellular environment per se therefore does not explain the lack of resistance.Second, resistance genes might reduce the viability of obligate intracellular bacteria. Few antibiotic-resistance genes have been described in obligate intracellular bacteria and the location of these genes in relation to the bacterial genes necessary for cell-dependency functions is unknown. The insertion of resistance genes in these bacteria has only been described for isolates subjected to repeated electroporation. The small genome of these bacteria (∼1100 kb for Rickettsia spp.), and the greater proportion of genome taken up by vital dependency genes, could inevitably lead to mutations, including antibiotic-resistance mutations, being more likely to be disruptive. It is also likely that the nature of cell dependency in these bacteria makes the mechanism of action of some antibiotic-resistance genes more likely to interfere with bacterial metabolism at the ribosomal and other cellular levels. For example, resistance mutations affecting the bacterial membranes or ribosomes could lead to an inability to process the necessary metabolic intermediates and/or ATP within the cell and on the ribosomes after these molecules are transported whole into the bacterium from the host cell if they resemble antibiotic molecules.Third, the altered metabolism of obligate intracellular bacteria might reduce their ability to utilize resistance genes. For example, the development of resistance to tetracyclines or macrolides by efflux mechanisms requires a consumption of bacterial energy that might not be readily possible in obligate intracellular bacteria, which generally derive energy from host cell sources. In the few studies of suggested erythromycin- and tetracycline-resistant strains of these bacteria, their growth indices were considerably reduced compared with wild-type strains16.xPartial characterization of Chlamydia trachomatis isolates resistant to multiple antibiotics. Jones, R.B. et al. J. Infect. Dis. 1990; 162: 1309–1315Crossref | PubMed | Scopus (103)See all References, 17.xProperties in culture and persistence in cotton rats of the Rickettsia prowazekii vaccine strain E and its mutants. Ignatovich, V.F. et al. Acta Virol. 1990; 34: 171–177PubMedSee all References.If this set of assumptions is partly correct, then functional pathways of resistance involving minor mutations of extra-ribosomal genes, which do not consume energy, should still evolve in obligate intracellular bacteria. Indeed, simple mutations in the rifampin site in rickettsial RNA polymerase genes are now known21xCharacterization of mutations in the rpoB gene in naturally rifampin-resistant Rickettsia species. Drancoult, M. and Raoult, D. Antimicrob. Agents Chemother. 1999; 43: 2400–2403PubMedSee all References21. Similarly, the identification of fluoroquinolone resistance components in DNA gyrase genes of intracellular bacteria is a rapidly expanding area.In conclusion, the use of pharmacokinetic and cell-culture models for MICs has not only been generally successful in predicting useful antibiotics but has also mapped their continuing usefulness. A detailed understanding of the interactions between the host cells, the bacterial ribosomes and the antibiotics could point to potentially advantageous strategies for use of these drugs against other bacteria, as well as pinpoint why these bacteria have failed to exhibit antibiotic resistance.