Mechanisms of resistance to antibiotics

Microbial resistance to antibiotics is manifested by changes in antibiotic permeability, alteration of target molecules, enzymatic degradation of the antibiotics, and efflux of antimicrobials from the cytosol. Bacteria and other microorganisms use all of these mechanisms to evade the toxic effects of antibiotics. Recent research on the molecular aspects of these mechanisms, often informed by atomic resolution structures of proteins, enzymes and nucleic acids involved in these processes, has deepened our understanding of antibiotic action and resistance and, in several cases, spurred the development of strategies to overcome resistance in vitro and in vivo.     

Resistance of Shigella to antibiotics

Antibiotic sensitivity of 104 Shigella clinical strains and 104 Escherichia coli strains isolated from patients with acute dysentery not treated with antibiotics in 1986-1987 was studied. It was shown that 100 per cent of the dysentery pathogens and colon bacilli were antibiotic resistant. Strains resistant simultaneously to chloramphenicol, ampicillin, streptomycin, tetracycline, monomycin and kanamycin were the most frequent among the dysentery pathogens. Colon bacilli and dysentery pathogens isolated from the same patient had specific sets of antibiotic resistance markers. Pathogenetic therapy of dysentery and exclusion of antibiotic use for several years did not result in lower numbers of Shigella antibiotic resistant strains.     

Sensitivity of Shigella to antibiotics]

Three hundred and twenty two Shigella cultures isolated from dysentery patients within 1986-1989 were tested with the use of standard paper disks for their sensitivity to levomycetin, streptomycin, tetracycline, monomycin, neomycin, kanamycin, erythromycin, gentamicin, carbenicillin, ampicillin, oxacillin, methicillin and doxycycline. The number of the cultures belonging to Shigella sonnei amounted to 85.1 per cent of the total number of the strains studied. 91.9, 89.5, 87.3, 87.3, 80.1 and 80.1 per cent of the cultures were sensitive to gentamicin, kanamycin, carbenicillin, neomycin, levomycetin and ampicillin, respectively. 99.4 per cent of the isolates were resistant to streptomycin and 97.2 per cent were resistant to tetracycline. The sensitivity to erythromycin remained rather high (70.2 per cent). The overwhelming majority of the Shigella sonnei isolates had multiple resistance.     

Beta-lactamases and bacterial resistance to antibiotics

The efficiency of β-lactam antibiotics, which are among our most useful chemotherapeutic weapons, is continuously challenged by the emergence of resistant bacterial strains. This is most often due to the production of β-lactamases by the resistant cells. These enzymes inactivate the antibiotics by hydrolysing the β-lactam amide bond. The elucidation of the structures of some β-lactamases by X-ray crystallography has provided precious insights into their catalytic mechanisms and revealed unsuspected similarities with the DD-transpeptidases, the bacterial enzymes which constitute the lethal targets of β-lactams. Despite numerous kinetic, structural and site-directed mutagenesis studies, we have not completely succeeded in explaining the diversity of the specificity profiles of β-lactamases and their surprising catalytic power. The solutions to these problems represent the cornerstones on which better antibiotics can be designed, hopefully on a rational basis.     

Growth-dependent bacterial susceptibility to ribosome-targeting antibiotics

Bacterial growth environment strongly influences the efficacy of antibiotic treatment, with slow growth often being associated with decreased susceptibility. Yet in many cases, the connection between antibiotic susceptibility and pathogen physiology remains unclear. We show that for ribosome-targeting antibiotics acting on Escherichia coli, a complex interplay exists between physiology and antibiotic action; for some antibiotics within this class, faster growth indeed increases susceptibility, but for other antibiotics, the opposite is true. Remarkably, these observations can be explained by a simple mathematical model that combines drug transport and binding with physiological constraints. Our model reveals that growth-dependent susceptibility is controlled by a single parameter characterizing the ‘reversibility’ of ribosome-targeting antibiotic transport and binding. This parameter provides a spectrum classification of antibiotic growth-dependent efficacy that appears to correspond at its extremes to existing binary classification schemes. In these limits, the model predicts universal, parameter-free limiting forms for growth inhibition curves. The model also leads to non-trivial predictions for the drug susceptibility of a translation mutant strain of E. coli, which we verify experimentally. Drug action and bacterial metabolism are mechanistically complex; nevertheless, this study illustrates how coarse-grained models can be used to integrate pathogen physiology into drug design and treatment strategies.     

Plasmid-determined streptococcal resistance to antibiotics]

The analysis of the genetic organization of the determinant ERLI by means of obtaining and studying the antibiotic sensitive mutants from the strain resistant to erythromycin and lincomycin provided experiment data in favour of the fact that inducable resistance to erythromycin and lincomycin determined by the plasmid might be defined by the same or closely linked genes.