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Advanced Drug Delivery Reviews (v.57, #10)
Mechanisms of antimicrobial resistance: opportunities for new targeted therapies
by Keith Poole Theme Editor; A. Denver Russell Theme Editor; Peter A. Lambert Theme Editor (pp. 1443-1445).
Antibiotic resistance—the problem intensifies by Stuart B. Levy (pp. 1446-1450).
While previously recognized antibiotic-resistant bacteria continue to increase in frequency and numbers globally, new resistance problems have recently emerged which further complicate and impede treatment of critical infectious diseases. Vancomycin resistance among Staphylococcus aureus, extended spectrum β-lactamases among gram-negative pathogens, and fluoroquinolone resistance among already multidrug-resistant Escherichia coli and Neisseria gonorrheae are adding to the toll of resistance on patients suffering with infectious diseases.
Keywords: Antibiotic resistance; MRSA; Fluoroquinolones; Vancomycin; Carbapenemases
Bacterial resistance to antibiotics: Enzymatic degradation and modification by Gerard D. Wright â?Ž (pp. 1451-1470).
Antibiotic resistance can occur via three general mechanisms: prevention of interaction of the drug with target, efflux of the antibiotic from the cell, and direct destruction or modification of the compound. This review discusses the latter mechanisms focusing on the chemical strategy of antibiotic inactivation; these include hydrolysis, group transfer, and redox mechanisms. While hydrolysis is especially important clinically, particularly as applied to β-lactam antibiotics, the group transfer approaches are the most diverse and include the modification by acyltransfer, phosphorylation, glycosylation, nucleotidylation, ribosylation, and thiol transfer. A unique feature of enzymes that physically modify antibiotics is that these mechanisms alone actively reduce the concentration of drugs in the local environment; therefore, they present a unique challenge to researchers and clinicians considering new approaches to anti-infective therapy. This review will present the current status of knowledge of these aspects of antibiotic resistance and discuss how a thorough understanding of resistance enzyme molecular mechanism, three-dimensional structure, and evolution can be leveraged in combating resistance.
Keywords: Antibiotic; Resistance; Hydrolase; Acetyltransferase; Kinase; Nucleotidyltransferase; Ribosyltransferase; Redox
Bacterial resistance to antibiotics: Modified target sites by Peter A. Lambert (pp. 1471-1485).
Alteration in the target sites of antibiotics is a common mechanism of resistance. Examples of clinical strains showing resistance can be found for every class of antibiotic, regardless of the mechanism of action. Target site changes often result from spontaneous mutation of a bacterial gene on the chromosome and selection in the presence of the antibiotic. Examples include mutations in RNA polymerase and DNA gyrase, resulting in resistance to the rifamycins and quinolones, respectively. In other cases, acquisition of resistance may involve transfer of resistance genes from other organisms by some form of genetic exchange (conjugation, transduction, or transformation). Examples of these mechanisms include acquisition of the mecA genes encoding methicillin resistance in Staphylococcus aureus and the various van genes in enterococci encoding resistance to glycopeptides.
Keywords: Bacterial resistance; Antibiotics; Modified targets; Resistance genes; Genetic exchange
Bacterial resistance to antibiotics: Active efflux and reduced uptake by Ayush Kumar; Herbert P. Schweizer (pp. 1486-1513).
Antibiotic resistance of bacterial pathogens is a fast emerging global crisis and an understanding of the underlying resistance mechanisms is paramount for design and development of new therapeutic strategies. Permeability barriers for and active efflux of drug molecules are two resistance mechanisms that have been implicated in various infectious outbreaks of antibiotic-resistant pathogens, suggesting that these mechanisms may be good targets for new drugs. The synergism of reduced uptake and efflux is most evident in the multiplicative action of the outer membrane permeability barrier and active efflux, which results in high-level intrinsic and/or acquired resistance in many clinically important Gram-negative bacteria. This review summarizes the current knowledge of these two important resistance mechanisms and potential strategies to overcome them. Recent advances in understanding the physical structures, function and regulation of efflux systems will facilitate exploitation of pumps as new drug targets.
Keywords: Outer membrane permeability; Porins; Active efflux; RND pumps; Regulation
Clinical impact and relevance of antibiotic resistance by G.L. French (pp. 1514-1527).
Increasing antimicrobial resistance and multiple resistance have resulted in increasing difficulties in the treatment of bacterial infections. Resistance leads to inappropriate empirical therapy, delay in starting effective treatment, and the use of less effective, more toxic, and more expensive drugs. Although studies are not always consistent, antimicrobial resistance in the infecting organisms is associated with treatment failure, prolonged or additional hospitalization, increased costs of care, and increased mortality. Additional costs and lost bed days are incurred by the need to control the spread of antimicrobial-resistant organisms within hospitals. All this has significant direct impact on patients and their families and also secondary effects on the cost effectiveness of healthcare delivery. There is an urgent need to control antimicrobial resistance by improved antibiotic usage and reduction of hospital cross-infection.
Keywords: Antimicrobial resistance; Treatment; Treatment outcomes; Healthcare costs
Novel target sites in bacteria for overcoming antibiotic resistance by Michael T. Black; John Hodgson (pp. 1528-1538).
Resistance to marketed antibiotics continues to increase. During the last 10 years some 200 bacterial genome sequences have become available, giving rise to expectations that genomics would provide a plethora of novel targets and hence a flood of new therapeutic agents. Contrary to some predictions the genomic effort has yet to yield a substantial number of novel class agents in clinical development. What are the reasons for the differences between expectations and reality? This article reviews what has been achieved in the exploitation of bacterial genomes for the discovery of novel antibacterials.
Keywords: Bacterial genomics; Target validation; Compound libraries; Lead identification; New class antibacterials
Biofilms and antibiotic therapy: Is there a role for combating bacterial resistance by the use of novel drug delivery systems? by Anthony W. Smith (pp. 1539-1550).
The conventional view of antibiotic resistance is one where bacteria exhibit significantly reduced susceptibility to antimicrobials in laboratory tests by mechanisms such as altered drug uptake, altered drug target and drug inactivation. Whilst these mechanisms undoubtedly make a major contribution to antibiotic failure in the clinic, the phenomenon of clinical failure in spite of sensitivity in laboratory tests is also well recognised. It is in this context that attention has focussed on bacteria growing as adherent biofilms, not only as the mode of growth of device-related infections associated for example with artificial joints and venous catheters, but also with other chronic infections such as those occurring in the respiratory tract. Growth as a biofilm almost always leads to a significant decrease in susceptibility to antimicrobial agents compared with cultures grown in suspension and, whilst there is no generally agreed mechanism for the resistance of biofilm bacteria, it is largely phenotypic. That is, when biofilm bacteria are grown in conventional laboratory suspension culture they become susceptible to antimicrobials. A number of elements in the process of biofilm formation have been studied as targets for novel drug delivery technologies. These include surface modification of devices to reduce bacterial attachment and biofilm development as well as incorporation of antimicrobials—again to prevent colonisation. Electrical approaches have been used either to release antimicrobials from device surfaces or to drive antimicrobials through the biofilm. Other technologies not specifically focussed on biofilms include aerosolized delivery of antibiotics to the lung and formulation into liposome and polymer-based vehicles. Liposomal systems have been widely studied, either to target antibiotics to the surface of bacterial biofilms, or by virtue of their property of being taken up cells of the reticuloendothelial system, to target antibiotics towards intracellular bacteria. Many polymer-based carrier systems have also been proposed, including those based on biodegradable polymers such as poly(lactide-co-glycolide) as well as thermoreversible hydrogels. Their contribution to the prevention or resolution of infection is reviewed.
Keywords: Biofilms; Phenotypic resistance; Material modification; Polyurethanes; Iontophoresis; Bio-electric effect; Pulsed electromagnetic fields; Ultrasound; Photodynamic enhancement; Liposomes; Pegylated liposomes; Biodegradable microspheres; Poly(lactide-co-glycolide); Hydroxyapatite; Halloysite; Electrospun fibrous scaffolds; Thermoreversible gels; Infection responsive systems; Aerosols
Corrigendum to “Real-time multiple-particle tracking: Applications to drug and gene delivery� [Advanced Drug Delivery Reviews 57(2005)63–78]
by Junghae Suh; Michelle Dawson; Justin Hanes (pp. 1551-1551).