Adverse effects of antimicrobials via predictable or idiosyncratic inhibition of host mitochondrial components.

This minireview explores mitochondria as a site for antibiotic-host interactions that lead to pathophysiologic responses manifested as nonantibacterial side effects. Mitochondrion-based side effects are possibly related to the notion that these organelles are archaic bacterial ancestors or commandeered remnants that have co-evolved in eukaryotic cells; thus, this minireview focuses on mitochondrial damage that may be analogous to the antibacterial effects of the drugs. Special attention is devoted to aminoglycosides, chloramphenicol, and fluoroquinolones and their respective single side effects related to mitochondrial disturbances. Linezolid/oxazolidinone multisystemic toxicity is also discussed. Aminoglycosides and oxazolidinones are inhibitors of bacterial ribosomes, and some of their side effects appear to be based on direct inhibition of mitochondrial ribosomes. Chloramphenicol and fluoroquinolones target bacterial ribosomes and gyrases/topoisomerases, respectively, both of which are present in mitochondria. However, the side effects of chloramphenicol and the fluoroquinolones appear to be based on idiosyncratic damage to host mitochondria. Nonetheless, it appears that mitochondrion-associated side effects are a potential aspect of antibiotics whose targets are shared by prokaryotes and mitochondria-an important consideration for future drug design.

Beta-lactam antibiotics prevent Salmonella-mediated bovine encephalopathy regardless of the ß-lactam resistance status of the bacteria.

This study assessed the capacity of ß-lactam antibiotics to prevent salmonella-mediated encephalopathy in calves given the putative neuroprotective effects of these drugs of increasing glutamate export from the brain. Both ampicillin and ceftiofur prevented the development of encephalopathy despite resistance of the inoculated Salmonella enterica serovar Saint-Paul isolate to both drugs. A glutamate receptor antagonist also prevented this salmonella-mediated encephalopathy. Glutamate exporters were hyper-expressed in the presence of ß-lactam antibiotics while a glutamate export inhibitor obviated the effects of these antibiotics, demonstrating a neuroprotective effect through glutamate export from the brain. The findings indicate that ß-lactam antibiotics remain an important treatment option for this atypical form of bovine salmonellosis.

Schistosoma-associated Salmonella resist antibiotics via specific fimbrial attachments to the flatworm.

BACKGROUND: Schistosomes are parasitic helminths that infect humans through dermo-invasion while in contaminated water. Salmonella are also a common water-borne human pathogen that infects the gastrointestinal tract via the oral route. Both pathogens eventually enter the systemic circulation as part of their respective disease processes. Concurrent Schistosoma-Salmonella infections are common and are complicated by the bacteria adhering to adult schistosomes present in the mesenteric vasculature. This interaction provides a refuge in which the bacterium can putatively evade antibiotic therapy and anthelmintic monotherapy can lead to a massive release of occult Salmonella. RESULTS: Using a novel antibiotic protection assay, our results reveal that Schistosoma-associated Salmonella are refractory to eight different antibiotics commonly used to treat salmonellosis. The efficacy of these antibiotics was decreased by a factor of 4 to 16 due to this association. Salmonella binding to schistosomes occurs via a specific fimbrial protein (FimH) present on the surface on the bacterium. This same fimbrial protein confers the ability of Salmonella to bind to mammalian cells. CONCLUSIONS: Salmonella can evade certain antibiotics by binding to Schistosoma. As a result, effective bactericidal concentrations of antibiotics are unfortunately above the achievable therapeutic levels of the drugs in co-infected individuals. Salmonella-Schistosoma binding is analogous to the adherence of Salmonella to cells lining the mammalian intestine. Perturbing this binding is the key to eliminating Salmonella that complicate schistosomiasis.

Evaluation of the pathogenicity and virulence of three strains of Salmonella organisms in calves and pigs.

OBJECTIVE: To assess in pigs the pathogenicity and virulence of 3 strains of Salmonella spp capable of causing atypical salmonellosis in cattle. ANIMALS: 36 Holstein calves and 72 pigs experimentally infected with Salmonella spp. PROCEDURES: Representative Salmonella strains associated with 3 new disease phenotypes (protozoa-mediated hypervirulence, multisystemic cytopathicity, and encephalopathy) that have been characterized in cattle during the past 10 years were orally inoculated into pigs. Clinical manifestations were compared with those observed in cattle. Samples were collected from various tissues, and the presence of Salmonella organisms was assessed qualitatively and quantitatively by use of Salmonella-selective media. RESULTS: Of the 3 unique Salmonella disease phenotypes observed in cattle, only protozoa-mediated hypervirulence was observed in pigs. Hypervirulence was related to a more rapid onset of disease and higher pathogen burden in pigs than in cattle. This phenotype was observed in pigs inoculated with multiresistant Salmonella enterica serotypes Typhimurium or Choleraesuis bearing the Salmonella genomic island 1 (SGI1) integron. CONCLUSIONS AND CLINICAL RELEVANCE: Salmonella hypervirulence was identified in pigs noculated with SGI1-bearing strains exposed to free-living protozoa. Additionally, an SGI1-bearing strain of Salmonella Choleraesuis was detected that resulted in augmented virulence in pigs. Therefore, it appeared that protozoa-associated salmonellosis was analogous in pigs and cattle. Salmonella-mediated encephalopathy and multisystemic cytopathicity did not appear to be relevant diseases in pigs.

Characterization of the retinal proteome during rod photoreceptor genesis.

BACKGROUND: The process of rod photoreceptor genesis, cell fate determination and differentiation is complex and multi-factorial. Previous studies have defined a model of photoreceptor differentiation that relies on intrinsic changes within the presumptive photoreceptor cells as well as changes in surrounding tissue that are extrinsic to the cell. We have used a proteomics approach to identify proteins that are dynamically expressed in the mouse retina during rod genesis and differentiation. FINDINGS: A series of six developmental ages from E13 to P5 were used to define changes in retinal protein expression during rod photoreceptor genesis and early differentiation. Retinal proteins were separated by isoelectric focus point and molecular weight. Gels were analyzed for changes in protein spot intensity across developmental time. Protein spots that peaked in expression at E17, P0 and P5 were picked from gels for identification. There were 239 spots that were picked for identification based on their dynamic expression during the developmental period of maximal rod photoreceptor genesis and differentiation. Of the 239 spots, 60 of them were reliably identified and represented a single protein. Ten proteins were represented by multiple spots, suggesting they were post-translationally modified. Of the 42 unique dynamically expressed proteins identified, 16 had been previously reported to be associated with the developing retina. CONCLUSIONS: Our results represent the first proteomics study of the developing mouse retina that includes prenatal development. We identified 26 dynamically expressed proteins in the developing mouse retina whose expression had not been previously associated with retinal development.

Identification of multiresistant Salmonella isolates capable of subsisting on antibiotics.

This study assessed the ability of Salmonella (572 isolates) to subsist on 12 different antibiotics. The majority (11/12) of the antibiotics enabled subsistence for at least 1 of 140 isolates. Furthermore, 40 isolates were able to subsist on more than one antibiotic. Antibiotic resistance and antibiotic subsistence do not appear to be equivalent.