Paris Descartes University

About: Paris Descartes University is a government organization based out in Paris, France. It is known for research contribution in the topics: Population & Transplantation. The organization has 20987 authors who have published 37456 publications receiving 1206222 citations. The organization is also known as: Université Paris V-Descartes & Université de Paris V.

Type II fatty acid synthesis is not a suitable antibiotic target for Gram-positive pathogens

Abstract: The type II fatty acid synthesis (FASII) pathway has been suggested to be a promising antimicrobial target, and the antibiotics platensimycin and platencin that target this pathway are claimed to be potentially effective against multiresistant Gram-positive bacteria. But a new study casts doubt on the value of this approach. Clinical isolates of a series of Gram-positive pathogens, including staphylococci, streptococci, pneumococci, and enterococci, are shown to overcome drug-induced blockade of FASII pathway inhibition when supplied with exogenous fatty acids either in laboratory growth medium or when infecting animals. Importantly, human serum is a highly effective source of fatty acids. The type II fatty acid biosynthesis pathway has been suggested to be a promising antimicrobial target. It is shown that major Gram-positive pathogen groups may circumvent the action of these antimicrobials by using host derived fatty acids instead, leaving these antibiotics ineffective. Antimicrobial drugs targeting the reportedly essential type II fatty acid synthesis (FASII) pathway1,2,3,4,5 have been recently acclaimed for their efficacy against infections caused by multiresistant Gram-positive bacteria6,7,8. Our findings show that the strategy for antibiotic development based on FASII pathway targets is fundamentally flawed by the fact that exogenous fatty acids fully bypass inhibition of this pathway in both in vitro and in vivo conditions. We demonstrate that major Gram-positive pathogens—such as streptococci, pneumococci, enterococci and staphylococci—overcome drug-induced FASII pathway inhibition when supplied with exogenous fatty acids, and human serum proves to be a highly effective source of fatty acids. For opportunist pathogen Streptococcus agalactiae, growth in serum leads to an overall decrease of FASII gene expression. No antibiotic inhibitor could have a stronger effect than the inactivation of the target gene, so we challenged the role of FASII using deletion mutants. Our results unequivocally show that the FASII target enzymes are dispensable in vivo during S. agalactiae infection. The results of this study largely compromise the use of FASII-based antimicrobials for treating sepsis caused by Gram-positive pathogens.

Uncoupling of type II collagen synthesis and degradation predicts progression of joint damage in patients with knee osteoarthritis

Abstract: Objective The hallmark of osteoarthritis (OA) is the loss of articular cartilage. This loss arises from an imbalance between cartilage synthesis and cartilage degradation over a variable period of time. The aims of this study were to investigate the rates of these processes in patients with knee OA using two new molecular markers and to investigate whether the combined use of these markers could predict the progression of joint damage evaluated by both radiography and arthroscopy of the joints during a period of 1 year. Methods Seventy-five patients with medial knee OA (51 women, 24 men; mean ± SD age 63 ± 8 years, mean ± SD disease duration 4.8 ± 5.2 years) were studied prospectively. At baseline, we measured serum levels of N-propeptide of type IIA procollagen (PIIANP) and urinary excretion of C-terminal crosslinking telopeptide of type II collagen (CTX-II) as markers of type II collagen synthesis and degradation, respectively. Joint space width (JSW) on radiography and medial chondropathy at arthroscopy (assessed using a 100-mm visual analog scale [VAS]) were measured in all patients at baseline and in 52 patients at 1 year. Progression of joint destruction was defined as a decrease of ≥0.5 mm in JSW on radiography and as increased chondropathy (an increase in the VAS score of >8.0 units) between the baseline and 1-year evaluations. Results At baseline, compared with 58 healthy age- and sex-matched controls, patients with knee OA had decreased serum levels of PIIANP (20 ng/ml versus 29 ng/ml; P < 0.001) and increased urinary excretion of CTX-II (618 ng/mmole creatinine [Cr] versus 367 ng/mmole Cr; P < 0.001). The highest discrimination between OA patients and controls was obtained by combining PIIANP and CTX-II in an uncoupling index (Z score CTX-II − Z score PIIANP), which yielded a mean Z score of 2.9 (P < 0.0001). Increased baseline values in the uncoupling index were associated with greater progression of joint damage evaluated either by changes in JSW (r = −0.46, P = 0.0016) or by VAS score (r = 0.36, P = 0.014). Patients with both low levels of PIIANP (less than or equal to the mean − 1 SD in controls) and high levels of CTX-II (greater than or equal to the mean + 1 SD in controls) had an 8-fold more rapid progression of joint damage than other patients (P = 0.012 and P < 0.0001 as assessed by radiography and arthroscopy, respectively) and had relative risks of progression of 2.9 (95% confidence interval [95% CI] 0.80–11.1) and 9.3 (95% CI 2.2–39) by radiography and arthroscopy, respectively. Conclusion Patients with knee OA are characterized by an uncoupling of type II collagen synthesis and degradation which can be detected by assays for serum PIIANP and urinary CTX-II. The combination of these two new markers could be useful for identifying knee OA patients at high risk for rapid progression of joint damage.