Resistance membrane-active antibiotics

Daptomycin binds to bacterial membranes resulting in depolarization, loss of membrane potential, and cell death. It has concentration-dependent bactericidal activity. Due to its unique mechanism of action, cross-resistance with other antibiotic classes seems not to occur, and there are no known resistance mechanisms. There were two cases (one S. aureus and the other E. faecalis) among more than 1000 cases treated in which resistance emerged during therapy. Staphylococci with decreased susceptibility to vancomycin have higher daptomycin MICs than fully susceptible strains. 

C. Mechanisms of Action and Resistance Beta-lactam antibiotics are bactericidal drugs. They act to inhibit cell wall synthesis by the following steps (Figure 43 2) (1) binding of the drug to specific receptors (penicillin-binding proteins PBPs) located in the bacterial cytoplasmic membrane (2) inhibition of transpeptidase enzymes that act to cross-link linear peptido-glycan chains which form part of the cell wall and (3) activation of autolytic enzymes that cause lesions in the bacterial cell wall. 

Antibiotic-resistant bacteria cause life-threatening infections in hospitals and society in general. There is a vital requirement to develop new antimicrobial agents, but this task involves extensive scientific trials. This chapter reviewed broad-spectrum polymeric antimicrobials, which are not susceptible to current resistance, and mechanisms of bacteria to mimic the antimicrobial action of natural HDP, which exert their effect by permeabilising the bacterial cytoplasmic membrane. Most cationic antimicrobial polymers appear to work in a manner similar to membrane-active AMP, such as magainin. The design and synthesis of different polymers, such as methacrylate-based copolymers, PPE, polynorbornene by-products, amphiphilc arylamide polymers and large polymers, have been studied as biomimetic polymers in different applications. 

Antibiotics may be defined as secondary metabolites of micro-organisms. In contrary to primary metabolites (proteins, carbohydrates, nucleic acids, lipids) which play an essential role in the growth and multiplication of cells secondary metabolites are of no importance in that respect. Antibiotics dispose of a relative low molecular mass and the ability to exhibit microbistatic or microbicidal efficacy in/on other microbe species by impairing the cell wall biosynthesis, the cytoplasmic membrane, the oxidative phophorylation. Because of there extremely high antimicrobial activity antibiotics are mainly used as chemotherapeuticals however, some antibiotics are also used in the food industry for the protection of food against deterioration e.g. Nisin (20.11.1.), Pimaricin (20.11.2.). But these applications will be more and more restricted or even completely banned as microbes may acquire resistance which represents a severe problem in chemotherapy with antibiotics. Acquired resistance is a consequence of the selection pressure on a microbe population in the presence of microbicides. Chemotherapy with an antibiotic the application of which has led to the selection of mutant resistant organisms is no longer successful. 

Finally, in an attempt to avoid the multiple intracellular resistance mechanisms that bacteria have evolved to inactivate AGs, several studies have demonstrated the potential of the positively charged AGs to be used as scalfolds for the development of membrane-targeting cationic amphiphilic antimicrobial agents. In these derivatives, hydrophobic residues are attached to one or more positions on the AG [23-25]. Several synthetic directions to develop AG-based cationic amphiphiles that wiU act as membrane-targeting antibiotics have resulted in AG derivatives with broad-spectrum activity against pathogenic bacteria with high levels of resistance to AGs and different levels of specificity for bacterial relative to eukaryotic membranes. 

Mupirocin is not related to any of the sys-temically used antibiotics. It is an inhibitor of bacterial protein synthesis and is especially active against gram-positive aerobic bacteria, e.g. methicillin-resistant S. aureus and group A beta-hemolytic streptococci. Absorption through the skin is minimal. Intranasal application may be associated with irritation of mucous membranes. 

Since the target enzymes of penicillins are membrane-bound proteins, an essential condition of antibacterial activity is that the antibiotic must be able to penetrate the outer spheres of the bacterial cell and reach its target in an active form. This problem is closely linked to the phenomenon of bacterial resistance (production of /3-lactamases), and justify the development of semisynthetic penicillins varying in the nature of the acylamino side chain at position C-6, and more recently the development of totally synthetic penems related to thienamycin (see Section 2.03.12.3). 

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