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This has led to multiple waves of semisynthetic 3-lactams over the 50 years of their clinical use. Scholar and Pratt (2000) note five categories of penicillins (Fig. 3.18A) based on narrow- versus broad-spectrum activities and whether there is antipseudomonal activity. The early synthetic side chains, phenylacetyl in penicillin G and phenoxyacetyl in penicillin V, gave narrow-spectrum drugs, active for example against streptococci and neisseria, and were 3-lactamase sensitive. Replacement of...

Other Targets of Antibacterial Drugs

The chapter opening figure is the fourth such diagram, are in each of chapters 3 through 6, that highlights the major grouping of antibiotics. This includes drugs that block precursor biosynthesis for nucleic acids as well as antibiotics that act to disrupt one or more aspects of bacterial membrane function. Folic acid metabolism the target for sulfamethoxazole-trimethoprim The class of synthetic chemicals in longest use as effective antibacterials are the sulfa drugs, first tested in the 1930s...

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Figure 1.1 Effects of bacteriostatic versus bactericidal antibiotics on a logarithmically growing bacterial culture. (From Scholar and Pratt 2000 , with permission.) drugs, introduced in the 1930s the quinolones, introduced in the 1960s and an oxazolidinone, approved in the United States in 2000. We will examine their discovery and development in parallel with those of natural antibiotics. The purpose and origin of the synthetic antibiotics is clear they emanate from medicinal chemistry...

Antibiotics targeted against the ribosome

The X-ray structures of the 30S and 50S ribosomal subunits and the full 70S complexes (chapter 4) are sure to aid in assay development and evaluation of new antibiotics that bind both at the classical sites and nonclassical sites in either the 16S or 23S rRNA molecules, which together make up two-thirds of the mass of the ribosome. The region of domain V of the 23S rRNA includes the peptidyltransferase center from the peptidyltransferase site to the beginning of the exit tunnel for the nascent...

Medical consequences of antibiotic use in agriculture

While hospitals are clearly fertile arenas for selection of antibiotic-resistant pathogenic bacteria, a complementary arena that has been understood for decades is the use of antibiotics in animal feed, for growth promotion and infectious disease prophylaxis (see Witte, 1998). The spread of resistance genes on transposons and plasmids (Davis and Lederberg, 2000 Levy, 1998) means that food animals are significant reservoirs for transmission of zoonotic pathogens, as detailed above for the spread...

New Looks at Targets

Defining new targets from bacterial genomics The goal in contemporary antibacterial target selections to maximize the chance that new drugs can be found and developed begins with bioinformatics to look for open reading frames (ORFs) conserved across the potential bacterial target organisms, from every bacterium in the most general case to all gram-positive or all gram-negative organisms as smaller categories that may still be worth attacking. A second desirable bioinformatics criterion is that...

Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria

This chapter is the first of three (chapters 8 to 10) that deal with the three major mechanisms of antibiotic resistance. The chapter opening figure highlights a section of Fig. 2.2 that summarizes resistance by antibiotic modification. Enzymatic inactivation of antibiotics occurs with several of the natural product antibiotic classes but has not yet been observed as a major route of resistance development for the classes of synthetic antibacterials the sulfamethoxazole-trimethoprim...

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Figure 9.4 Schematic of an ABC transporter. (A) The MsbA dimer and its orientation towards membrane bilayer leaflets. (B) Schematic of lipid A transport by E. coli MsbA. (From Chang and Roth 2001 , with permission.) Figure 9.4 Schematic of an ABC transporter. (A) The MsbA dimer and its orientation towards membrane bilayer leaflets. (B) Schematic of lipid A transport by E. coli MsbA. (From Chang and Roth 2001 , with permission.) tion and the number and orientation of helices in BtuC are...

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Products that inhibit MraY action include mureidomycins A to F (Fig. 3.9B) (Lee and Hecker, 1999), liposidomycins, and tunicamycin, all uridyl peptide antibiotics that are thought to compete with the UDP-muramyl pentapeptide substrate for MraY. While tunicamycin also inhibits the eukaryotic biosynthesis of dolichol-PP-GlcNAc in glycoprotein biosynthesis, the liposidomycins and mureidomycins are selective for inhibition of the prokaryotic MraY (Lee and Hecker, 1999). They may offer starting...

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Figure 2.1 Electron microscopic view of some bacterial pathogens. (A) Mycobacterium tuberculosis in sputum (B) Enterococcus faecalis (C) Streptococcus pneumoniae (D) Staphylococcus aureus (E) Pseudomonas fluorescens (F) Haemophilus influenzae. (Courtesy Visuals Unlimited all D. M. Phillips except panel A M. Abbey.) antibiotic target in the recipient bacteria. The 3-lactam antibiotics have progressed through several stages of optimization of the five-ring penicillins and up to four iterations of...

Strategies for control of antimicrobial drug resistance

Over the past few years there has been an increase in the understanding of the need for revised antibiotic policies to control antibiotic resistance (Gould, 1999 Kunin, 1997 Levy, 1992 McGowan and Tenover, 1997 Shlaes et al., 1997a, 1997b). This has involved both clinical and epidemiologic approaches to evaluate the main routes and causes for appearance and spread of antimicrobial resistance in hospital organisms and in community settings, with appreciation of population dynamics. Clinical...

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Nora Bacterial Efflux Pump

From Putman et al. 2000 , with permission. From Putman et al. 2000 , with permission. Figure 9.1 Four protein subfamilies of proton-dependent efflux pumps and the ATPase family of efflux pump in antibiotic resistance. (From Paulsen et al. 1996 , with permission.) Figure 9.1 Four protein subfamilies of proton-dependent efflux pumps and the ATPase family of efflux pump in antibiotic resistance. (From Paulsen et al. 1996 , with permission.) or the RND (resistance nodulation cell division) family,...

Natural and Producer Immunity versus Acquired Resistance

During the five to six decades that antibiotics have been in ever-widening therapeutic use, the development of antibiotic resistance has followed. The historical observations are that whenever a new antibiotic, broader-spectrum forms of an existing antibiotic, or a new class of antibiotics is introduced into widespread use in people, clinically significant resistance appears. It may be a matter of months penicillin resistance was detected as early as 1945 or it could take years vancomycin...

Antibiotics That Block DNA Replication and Repair the Quinolones

Anthrax Replication Table

The third major functional grouping of antibiotics are those that block DNA replication and repair. The figure on the facing page highlights the relevant subsection of Fig. 2.2 and the inhibition of DNA and RNA synthesis by the quinolone and rifamycin classes of antibacterial drugs. The rifamycin class of peptide polyketide antibiotics are taken up in the next chapter. DNA gyrase as a target of quinolones and coumarins Inhibition of DNA replication and repair enzymes would seem a logical target...