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Because of the wealth of information within the covers of this important book, all those involved in research into drug action and development, whether in the pharmaceutical industry or academia, will find Biochemistry and Molecular Biology of Antimicrobial Drug Action invaluable. It should also be on the shelves of all libraries, in university medical schools and departments of biological sciences, biochemistry and pharmacology. Skip to main content Skip to table of contents. Advertisement Hide. Authors view affiliations T.

Franklin G. Front Matter Pages i-x. The development of antimicrobial agents past, present and future. Pages Considering the working principles of antimicrobial macromolecular systems, the design procedures can be divided in three categories Figure 4 , as follows:. Schematic representation of the design possibilities of antibacterial polymers based on the working principles of macromolecular systems.

Polymeric biocides are macromolecules constituted of bioactive repeating units, namely polymers, represent multiple interconnected biocides, which act similarly to the monomers. They can be designed by synthetic routes that yield macromolecules with antimicrobial activity. Their function is not always understood. For instance, polymers and copolymers prepared from 2-methacryloxytroponones are able to kill bacteria. The design of this category of antimicrobial polymers is based on the concept that biocidal groups attached to a polymer act in the same way as analogous low molecular weight compounds, demonstrating that the repeating unit is a biocide.

Taking into account the sterical hindrance exerted by the macromolecular backbone, polymeric biocides are expected to be less active than the respective low molecular weight compounds. Literature [ 20 ] shows possibility to polymerize antibiotics maintaining their activity at the polymer backbone, e. Also, polymers with side groups based on hydrophobic quaternary ammonium functions can be considered as polymeric biocides.

The biocidal polymers preparation steps require the embodiment of the active principle in the whole macromolecule. It does not necessarily demand the use of antimicrobial repeating units. Microbial cells generally carry a negative net charge at the surface due to their membrane proteins.

These charges are prepresented by teichoic acids in case of Gram-positive bacteria, and phospholipids at the outer membrane in case of Gram-negative bacteria. Therefore, polycations are attracted and if they have a proportionate amphiphilic character, they are able to destroy the cytoplasmic membrane, resulting in cell death. The most antimicrobial polycations contain quaternary ammonium [ 21 ] and phosphonium [ 22 ], tertiary sulfonium [ 23 ], and guanidinium functions. Biocidal macromolecules that do not contain biocidal repeating units present antimicrobial activity that originates from the whole molecule.

The biocidal repeating units are not required if the polymer backbone exhibits a hydrophobic character. On the other hand, polymers with a hydrophilic polymer backbone demand a hydrophobic region parallel to the backbone, which is provided by the hydrophobic side groups. Polymeric biocides are efficient when cationic groups are placed along the polymer backbone, but the good results are obtained also for polymers having only one biocidal end group. These polymers are obtained by cationic ring-opening polymerization of 2-alkyl-1,3-oxazolines and terminating the macromolecule with a cationic surfactant.

The advantage of this preparation technique is the controlled introduction of a specific group at one end and another group at the opposite end of the macromolecules by selecting a suitable initiator and termination agent. Biocide-releasing polymers do not act through the actual polymeric part, but the latter represents a carrier for biocides that are transferred through different mechanisms like diffusion to the infected area.

Such polymers are usually the most active systems, because they can release their biocides close to the cell in high local concentrations. The biocide-releasing macromolecules were prepared for the first time through polymerization of salicylic acid subjected to degradation, which enables the controlled releasing of salicylic acid. Several types of biocidal polymers have been designed to release chlorine, nitric oxide, phenols, or singlet oxygen. Another class of biocide-releasing polymers is the contact-active ones, like tributyltin esters of polyacrylates.

Natural polymers, such as collagen, can serve as antibacterial drug carrier. The latter can be complexed to the polymer through direct binding of the biocide to free amino or carboxylic groups of the collagen molecule [ 24 ]. The diffusion is the main process that assures the release of the drug after implantation or injection. The design of the sponge and the drug incorporation by colyophilization allow the uniform distribution of the drug within the spongy matrix.

This also ensures an equal drug dose applied per square centimeter of the treated surface. Pore size of natural polymer sponges can be controlled by the lyophilization process [ 24 ]. On the other hand, synthetic copolymers, like epoxy-functional poly dimethylsiloxane can be processed to favor the attachment i.

The reaction occurred via ring-opening of epoxy groups by the carboxylic acid group of levofloxacin, the tether produced was an ester-functional tether.


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Compared to a control coating generated by simply blending levofloxacin into a polysiloxane, the samples with tethered levofloxacin moieties presented uniform distribution of levofloxacin, higher initial kill, and sustained antimicrobial surface activity. The antimicrobial agents can be introduced into polymer microparticles. The co-precipitation of CaCO 3 and silver nanoparticles SNPs in the presence of poly sodium 4-styrenesulfonate leads to a system that enables sustained release of biocide [ 26 ]. Microbiological tests confirmed the effectiveness of these microparticles as an antibacterial agent.

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This designed material can be stored as a dry powder and subsequently re-suspended in water without the risk of losing its antimicrobial activity. Plasma is widely used as a tool for polymer functionalization with biocide agents. SNPs-based antibacterial coatings can protect eukaryotic cells from SNPs-related toxic effects, while preserving antibacterial efficiency [ 27 ]. Even so, the antibacterial activity is maintained to planktonic bacteria living in the near surroundings of the material.

The SNPs-based materials also revealed antibacterial effect on adhered bacteria [ 28 , 29 ]. Their number was significantly reduced compared to pure HA plasma polymer and the physiology of the bacteria was affected. The number of adhered bacteria is directly diminished with thickness of the second HA layer.

Bacterial agents can cause both superficial and serious systemic diseases, generating infections anywhere, including in hospitals. Infections involve the formation of in vitro or in vivo bio-clusters on implanted devices, such as catheters or prosthetic heart valves. These bacterial agents formed in vitro on different bio-materials consist of micro-colonies which are resistant to a range of antibacterial agents, through several mechanisms of resistance [ 30 , 31 ].

Microorganisms can be organized as biofilms, including pathogens, thus offering a means to protect themselves against antimicrobial agents. Several mechanisms have been proposed to explain this phenomenon of resistance within biofilms, such as:. Implications of biofilm formation are that alternative control strategies must be devised both for testing the susceptibility of the organisms within the biofilm and for treating the established biofilm to alter its structure. A number of testing protocols have been developed. The effective treatment strategies include antimicrobials or other agents that can penetrate and kill the biofilm organisms, or treatments that can disrupt or target specific components of the biofilm matrix [ 32 ].

Recent studies on bacterial and fungal species suggest that extensive and striking interactions occur between the prokaryotic and eukaryotic cells [ 33 ]. Also, their possible mechanisms of resistance vary with the nature of the administered antimicrobial agent, are not fully understood, and are grouped in literature taking into account [ 34 ] the following parameters:.

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The methods of selection of drugs to be considerate in case of combined devices are provided by Venn diagrama diagram Figure 5 that shows all possible logical relations between finite collections of different sets, including the pharmaceutical device pharmacokinetics, pharmacodynamics, biopharmaceutics, therapeutic dose , medical device type and class of device, manufacturing process, testing requirements , and combination device perspective local drug effects, controlled release combined manufactured methods, business drivers, clinical concerns [ 33 ].

The Venn diagram for perspective of devices and combined devices: a pharmaceutical device; b medical device; and c combination device. The considerable interest exists in combination devices that include the type of peripheral stents, orthopedics, indwelling catheters, dental implants, surgical meshes, wound dressings, ophthalmic implants, sutures, and even artificial organs [ 35 , 36 ].

The physicochemical properties of the drugs used in combination devices, as well as their location in vivo or in vitro, include the knowledge of their antibacterial activity. Table 1 presents the beneficial effects of treatment with antimicrobial agents against various types of bacteria, associated as biofilms.

However, besides the beneficial treatments, there are some secondary effects produced by antimicrobial drugs. The fluoroquinolone class of antibacterial drugs that determine adverse events include central nervous system toxicity, phototoxicity, and in some cases electrocardiographic changes. Some side-effects of the quinolones are class effects, and cannot be modulated by molecular variation.

These include gastrointestinal irritation and arthropathy. Moreover, gastrointestinal prokinetics, such as metoclopramide, cisapride and levosulpiride, are widely used for the management of functional gut disorders. Recent investigations revealed that cisapride a partial 5-HT4 receptor agonist can generate dose-dependent cardiac adverse effects, including lengthening of the electrocardiographic QT interval, syncopal episodes, and ventricular dysrhythmias.

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Determination of the minimum inhibitory concentration, based on the activities of antibiotics against planktonic bacteria, is the standard assay for antibiotic susceptibility testing. In this context, the Calgary Biofilm Device is well recognized as a technology for the rapid and reproducible assay of biofilm susceptibilities to antibiotics, for the rational selection of antibiotics effective against microbial biofilms, and for the finding of new effective antibiotic compounds [ 8 ].

On the other hand, the antibiotic tolerance is defined as the ability of bacteria to survive but not grow in the presence of antibiotics. It is known that adherent bacteria on solid surfaces already have tolerance to antibiotics and depend essentially on the different stress conditions on antibiotic tolerance [ 47 ]. The rise in antibiotic resistance among pathogenic bacteria and the declining rate of novel drug discovery motivate recent studies to find new classes of antibacterial agents and novel drugs, in order to maintain the ability to treat infectious diseasesespecially those caused by multidrug-resistant organisms [ 48 ].

Research concerning the activity and design of cationic antimicrobial peptides and their mimics has produced several antimicrobial compounds with good antibacterial activity and elucidated trends of increasing activity and specificity. Applications are numerous, including antimicrobial surfaces [ 49 ] and conjugates in targeted therapy [ 50 ]. The interest in cationic antimicrobial peptides opens new perspectives in antimicrobial drug design.

The Hunter-killer peptides represent a novel class of targeted peptides that have demonstrated remarkable efficacy in several basic proof-of-principle paradigms including therapeutics for cancer [ 51 ], arthritis [ 52 ], prostate reduction [ 53 ], and obesity [ 54 ]. This technology uses similar way to encapsulate anticancer proteins, such as the small globular proteins. Development and evaluation of the next generation of Hunter-killer peptides with improved modulation of the absorption, distribution, metabolism, and excretion properties are studies currently underway. Host-defense peptides are present components of the innate immune system across all organisms.

These molecules have been widely studied for their activities, such as antimicrobial, antitumor, mitogenic, and chemical signaling properties. It is known that oligo-acyl-lysyls are synthetic mimics of host-defense peptides known to exert antibacterial activity both in cultures and in animal models of disease [ 56 ]. Data obtained with representative bacteria, including the Gram-negative bacterium Escherichia coli and the Gram-positive bacteria Listeria monocytogenes and Staphylococcus aureus , shows that the oligo-acyl-lysyls potency is affected by pH changes and subsides essentially throughout a wide range of salt concentrations and temperature, whereas antistaphyloccocal activity is vulnerable.

Also, in biomedical strategy concerning host-defense peptides, several short synthetic oligomers such as methacrylate, arylamide foldamers, and oligo-acyl-lysyls have attracted particular attention due to their lower cost and rapid structural optimization capabilities [ 57 ].

As a result of the appearance of multidrug-resistant bacteria, antimicrobial peptides have emerged as one of the leading prospects for drug development. Antimicrobial peptides are retained in a wide range of organisms as a defense mechanism against a broad array of microbial targets. These peptides vary in size, sequence, and efficacy, allowing a good interaction with the charged bacterial membrane [ 59 ]. In this context, to mimic the amphiphilic nature of antimicrobial peptides, arylamide foldamers were prepared, that demonstrated bactericidal activity against both Gram-negative and Gram-positive strains, without many of the drawbacks of natural antimicrobial peptides [ 60 ].

The emergence and spread of antibiotic resistance represent an alarming concern in clinical practice. From this reason, the antimicrobial agents are used to cover materials and medical devices as a prophylaxis to prevent bacteria from growing or for therapeutic uses. A range of silver-coated or impregnated dressings are commercially available for use. The rapidity and extent of killing of these pathogens evaluated under in vitro conditions shows that silver-impregnated dressings exert bactericidal activity, particularly against Gram-negative bacteria, including Enterobacter species, Proteus species, and Escherichia coli.

Therefore, the incorporation of silver for dressings or as coating on medical products plays an important role in the domain of antimicrobial agents [ 61 ]. On the other hand, it is known that infection is the most common cause of biomaterial implant failure in modern medicine [ 62 ]. Gram-positive Staphylococcus aureus and Staphylococcus epidermidis are the predominant infecting organisms, followed by Gram-negative bacilli like Escherichia coli and Pseudomonas aeruginosa. A possible approach to prevent biomaterial-centered infections is to render the biomaterial surface antimicrobial properties by functionalization with, e.

Quaternary ammonium-functionalized surfaces have a high positive surface charge, and thus exert a strong adhesive force on negatively charged bacteria which are proposed to inhibit surface growth of bacteria. The main mechanisms of action of antibacterial drugs Figure 6 can be classified as follows:.


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  • Several in vitro and in vivo studies show that methicillin-resistant Staphylococcus aureus MRSA remains a leading cause of bacterial infections worldwide, ranging from minor skin and soft tissue infections to more severe conditions such as bacteremia and infective endocarditis [ 63 ]. The molecules currently under pre-clinical and clinical investigation that are active against MRSA, with special emphasis on their mechanism of action are grouped as follows:. Learn More - opens in a new window or tab Any international postage and import charges are paid in part to Pitney Bowes Inc.

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