ABSTRACT
The type III secretion system (T3SS) is highly conserved in many Gram-negative pathogenic bacteria and functions as an injector of bacterial proteins (effectors) into host cells. T3SSs are involved in establishing disease processes, but this machinery is not essential for bacterial growth or homeostasis. Thus, T3SS is expected to be a candidate therapeutic target, and inhibitors of T3SSs could potentially reduce virulence without causing bacterial death, thereby avoiding any subsequent development of resistance. We identified a linear polyketide compound, aurodox, as a specific T3SS inhibitor from the culture broth of Streptomyces sp. using a screening system for the T3SS-mediated hemolysis of enteropathogenic Escherichia coli (EPEC) established by our group. Aurodox strongly inhibited T3SS-mediated hemolysis with an IC(50) value of 1.5 µg ml(-1) without affecting bacterial growth in liquid media. We also demonstrated that aurodox specifically inhibits the secretion of type III-secreted proteins such as EspB, EspF and Map, without affecting the expression of the housekeeping protein GroEL. Furthermore, an in vivo infection study using mice clearly indicated that the administration of aurodox allowed the mice to survive a lethal dose of Citrobactor rodentium, a model bacterium for human pathogens such as EPEC. Thus, our in vivo study directly demonstrated for the first time that this putative T3SS inhibitor can be applied as a novel class of anti-infective agents.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Aurodox/therapeutic use , Bacterial Proteins/antagonists & inhibitors , Citrobacter rodentium/drug effects , Enterobacteriaceae Infections/drug therapy , Membrane Transport Proteins/metabolism , Animals , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Aurodox/isolation & purification , Aurodox/pharmacology , Drug Evaluation, Preclinical , Escherichia coli/drug effects , Female , Hemolysis/drug effects , Inhibitory Concentration 50 , Mice , Streptomyces/metabolism , Survival Analysis , Treatment OutcomeABSTRACT
La artritis séptica por Salmonella no typhi representa menos del 2 por ciento del total de las artritis sépticas1. El serotipo etiológico más frecuente es Salmonella enteritidis. Su clínica, precedida o no de una gastroenteritis, no difiere de otras artritis sépticas, y se presenta con fiebre y sinovitis monoarticular, habitualmente en rodilla, cadera y hombro. La inmunosupresión (terapéutica, virus de la inmunodeficiencia humana [VIH], lupus eritematoso sistémico [LES], etc.) es el principal factor de riesgo en su desarrollo. La drepanocitosis, la hemofilia, las neoplasias y las edades extremas de la vida también predisponen a su aparición. El diagnóstico se realiza por cultivo de líquido sinovial. El tratamiento está condicionado por las resistencias descritas a múltiples antibióticos, incluso a los más actuales, como son las fluoroquinolonas. Las complicaciones locales más frecuentes son la limitación residual funcional y la osteomielitis. El pronóstico, marcado por la enfermedad de base, presenta una elevada mortalidad (AU)
Subject(s)
Male , Middle Aged , Humans , Arthritis/complications , Arthritis/diagnosis , Arthritis/therapy , Salmonella Infections/complications , Salmonella Infections/diagnosis , Salmonella/isolation & purification , Salmonella/pathogenicity , Gastroenteritis/complications , Gastroenteritis/diagnosis , Immunosuppression Therapy/methods , Risk Factors , Tomography, Emission-Computed/methods , Aurodox/therapeutic use , Ciprofloxacin/therapeutic use , Fever/complications , Fever/diagnosis , Synovitis/complications , Synovitis/diagnosis , Hemophilia A/complications , Hemophilia A/diagnosisABSTRACT
Antibiotic SB22484 is a novel member of the aurodox type antibiotic group produced in submerged-fermentation cultures of Streptomyces sp. NRRL 15496. The antibiotic complex is composed of two pairs of isomers with MW's of 752 and 766. The individual isomers, which were separated by preparative HPLC, equilibrate to a mixture of the isomer pair when left in aqueous solution. In vitro, SB22484 antibiotics strongly inhibited neisseriae and were also active against Streptococci, Ureaplasma urealyticum and Haemophilus influenzae.
