The worldwide increase in the prevalence of multi-antibiotic–resistant bacteria has threatened the physician’s ability to provide appropriate therapy for infections. The relationship between antimicrobial drug concentration and infecting pathogen population reduction is of primary interest. Using data derived from mice infected with the bacterium Pseudomonas aeruginosa and treated with a fluoroquinolone antibiotic, a mathematical model was developed that described relationships between antimicrobial drug exposures and changes in drug-susceptible and -resistant bacterial subpopulations at an infection site. Dosing regimens and consequent drug exposures that amplify or suppress the emergence of resistant bacterial subpopulations were identified and prospectively validated. Resistant clones selected in vivo by suboptimal regimens were characterized. No mutations were identified in the quinolone resistance–determining regions of gyrA/B or parC/E. However, all resistant clones demonstrated efflux pump overexpression. At base line, MexAB-OprM, MexCD-OprJ, and MexEF-OprN were represented in the drug-resistant population. After 28 hours of therapy, MexCD-OprJ became the predominant pump expressed in the resistant clones. The likelihood of achieving resistance-suppression exposure in humans with a clinically prescribed antibiotic dose was determined. The methods developed in this study provide insight regarding how mathematical models can be used to identify rational dosing regimens that suppress the amplification of the resistant mutant population.
Nelson Jumbe, Arnold Louie, Robert Leary, Weiguo Liu, Mark R. Deziel, Vincent H. Tam, Reetu Bachhawat, Christopher Freeman, James B. Kahn, Karen Bush, Michael N. Dudley, Michael H. Miller, George L. Drusano
Acute rheumatic fever is a serious autoimmune sequel of Streptococcus pyogenes infection. This study shows that serotype M3 and M18 S. pyogenes isolated during outbreaks of rheumatic fever have the unique capability to bind and aggregate human basement membrane collagen type IV. M3 protein is identified as collagen-binding factor of M3 streptococci, whereas M18 isolates bind collagen through a hyaluronic acid capsule, revealing a novel function for M3 protein and capsule. Following in vivo mouse passage, conversion of a nonencapsulated and collagen-binding negative M1 S. pyogenes into an encapsulated, collagen-binding strain further supports the crucial role of capsule in mediating collagen binding. Collagen binding represents a novel colonization mechanism, as it is demonstrated that S. pyogenes bind to collagen matrix in vitro and in vivo. Moreover, immunization of mice with purified recombinant M3 protein led to the generation of anti–collagen type IV antibodies. Finally, sera from acute rheumatic fever patients had significantly increased titers of anti–collagen type IV antibodies as compared with healthy controls. These findings may suggest a link between the potential of rheumatogenic S. pyogenes isolates to bind collagen, and the presence of collagen-reactive autoantibodies in the serum of rheumatic fever patients, which may form a basis for post-streptococcal rheumatic disease. These anti-collagen antibodies may form a basis for poststreptococcal rheumatic disease.
Katrin Dinkla, Manfred Rohde, Wouter T.M. Jansen, Edward L. Kaplan, Gursharan S. Chhatwal, Susanne R. Talay
We previously reported that laboratory reference strains of Chlamydia trachomatis differing in infection organotropism correlated with inactivating mutations in the pathogen’s tryptophan synthase (trpBA) genes. Here, we have applied functional genomics to extend this work and find that the paradigm established for reference serovars also applies to clinical isolates — specifically, all ocular trachoma isolates tested have inactivating mutations in the synthase, whereas all genital isolates encode a functional enzyme. Moreover, functional enzyme activity was directly correlated to IFN-γ resistance through an indole rescue mechanism. Hence, a strong selective pressure exists for genital strains to maintain a functional synthase capable of using indole for tryptophan biosynthesis. The fact that ocular serovars (serovar B) isolated from the genital tract were found to possess a functional synthase provided further persuasive evidence of this association. These results argue that there is an important host-parasite relationship between chlamydial genital strains and the human host that determines organotropism of infection and the pathophysiology of disease. We speculate that this relationship involves the production of indole by components of the vaginal microbial flora, allowing chlamydiae to escape IFN-γ–mediated eradication and thus establish persistent infection.
Harlan D. Caldwell, Heidi Wood, Debbie Crane, Robin Bailey, Robert B. Jones, David Mabey, Ian Maclean, Zeena Mohammed, Rosanna Peeling, Christine Roshick, Julius Schachter, Anthony W. Solomon, Walter E. Stamm, Robert J. Suchland, Lacey Taylor, Sheila K. West, Tom C. Quinn, Robert J. Belland, Grant McClarty
Enrique Lara-Pezzi, Maria Victoria Gómez-Gaviro, Beatriz G. Gálvez, Emilia Mira, Miguel A. Iñiguez, Manuel Fresno, Carlos Martínez-A., Alicia G. Arroyo, Manuel López-Cabrera
Stephanie L. Constant, Jennifer L. Brogdon, Damani A. Piggott, Christina A. Herrick, Irene Visintin, Nancy H. Ruddle, Kim Bottomly
Lawrence Y. Lee, Yuko J. Miyamoto, Bradley W. McIntyre, Magnus Höök, Kirk W. McCrea, Damien McDevitt, Eric L. Brown
Yasushi Hanakawa, Norman M. Schechter, Chenyan Lin, Luis Garza, Hong Li, Takayuki Yamaguchi, Yasuyuki Fudaba, Koji Nishifuji, Motoyuki Sugai, Masayuki Amagai, John R. Stanley
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