21 research outputs found
Efflux pump inhibitors (EPIs) as new antimicrobial agents against Pseudomonas aeruginosa
Pseudomonas aeruginosa is an opportunistic human pathogen and one of the leading causes of nosocomial infections worldwide. The difficulty in treatment of pseudomonas infections arises from being multidrug resistant (MDR) and exhibits resistance to most antimicrobial agents due to the expression of different mechanisms overcoming their effects. Of these resistance mechanisms, the active efflux pumps in Pseudomonas aeruginosa that belong to the resistance nodulation division (RND) plays a very important role in extruding the antibiotics outside the bacterial cells providing a protective means against their antibacterial activity. Beside its role against the antimicrobial agents, these pumps can extrude biocides, detergents, and other metabolic inhibitors. It is clear that efflux pumps can be targets for new antimicrobial agents. Peptidomimetic compounds such as phenylalanine arginyl β-naphthylamide (PAβN) have been introduced as efflux pump inhibitors (EPIs); their mechanism of action is through competitive inhibition with antibiotics on the efflux pump resulting in increased intracellular concentration of antibiotic, hence, restoring its antibacterial activity. The advantage of EPIs is the difficulty to develop bacterial resistance against them, but the disadvantage is their toxic property hindering their clinical application. The structure activity relationship of these compounds showed other derivatives from PAβN that are higher in their activity with higher solubility in biological fluids and decreased toxicity level. This raises further questions on how can we compact Pseudomonas infections. Of particular importance, the recent resurgence in the use of older antibiotics such as polymyxins and probably applying stricter control measures in order to prevent their spread in clinical sittings
Anti-infectives in Drug Delivery-Overcoming the Gram-Negative Bacterial Cell Envelope.
Infectious diseases are becoming a major menace to the state of health worldwide, with difficulties in effective treatment especially of nosocomial infections caused by Gram-negative bacteria being increasingly reported. Inadequate permeation of anti-infectives into or across the Gram-negative bacterial cell envelope, due to its intrinsic barrier function as well as barrier enhancement mediated by resistance mechanisms, can be identified as one of the major reasons for insufficient therapeutic effects. Several in vitro, in silico, and in cellulo models are currently employed to increase the knowledge of anti-infective transport processes into or across the bacterial cell envelope; however, all such models exhibit drawbacks or have limitations with respect to the information they are able to provide. Thus, new approaches which allow for more comprehensive characterization of anti-infective permeation processes (and as such, would be usable as screening methods in early drug discovery and development) are desperately needed. Furthermore, delivery methods or technologies capable of enhancing anti-infective permeation into or across the bacterial cell envelope are required. In this respect, particle-based carrier systems have already been shown to provide the opportunity to overcome compound-related difficulties and allow for targeted delivery. In addition, formulations combining efflux pump inhibitors or antimicrobial peptides with anti-infectives show promise in the restoration of antibiotic activity in resistant bacterial strains. Despite considerable progress in this field however, the design of carriers to specifically enhance transport across the bacterial envelope or to target difficult-to-treat (e.g., intracellular) infections remains an urgently needed area of improvement. What follows is a summary and evaluation of the state of the art of both bacterial permeation models and advanced anti-infective formulation strategies, together with an outlook for future directions in these fields
Phosphodiesterase 4 inhibitors in chronic obstructive pulmonary disease: a new approach to oral treatment
Anti-Tubercular Drug Designing by Structure based Screening of Combinatorial Libraries
In the current study, the applicability and scope
of descriptor based QSAR models to complement virtual
screening using molecular docking approach have been
applied to identify potential virtual screening hits targeting
DNA gyrase A from Mycobacterium tuberculosis, an
effective and validated anti-mycobacterial target. Initially
QSAR models were developed against M. fortuitum and M.
smegmatis using a series of structurally related fluoroquinolone
derivatives as DNA gyrase inhibitors. Both the
QSAR models yielded significant cross validated Q(2)
values of 0.6715 and 0.6944 and R(2) values of 0.7250 and
0.7420, respectively. The statistically significant models
were validated by a test set of 22 compounds with
predictive R(2) value of 0.7562 and 0.7087 for M. fortuitum
and M. smegmatis respectively. To aid the creation of novel
antituberculosis compounds, combinatorial library was
developed on fluoroquinolone template to derive a data
set of 5280 compounds whose activity values have been
measured by the above models. Highly active compounds
predicted from the models were subjected to molecular
docking study to investigate the mechanism of drug
binding with the DNA gyrase A protein of M. tuberculosis
and the compounds showing similar type of binding
patterns with that of the existing drug molecules, like
sparfloxacin, were finally reported. It is seen that hydrophobic
characteristics of molecular structure together with
few hydrogen bond interactions are playing an essential
role in antimicrobial activity for the fluoroquinolone derivatives. A representative set of seven compounds with
high predicted MIC values were sorted out in the present
study