Antibacterial protein structure

Genes Specifying Antibacterial Protein Structure. Adult flies and larvae of Drosophila and Ceratitis do not normally contain in their blood proteins that specifically kill bacteria. However, when animals are inoculated with Enterobacter cloacae, potent antibacterial activity appears in the blood (11,12,17,18). Antibacterial activity is detected in the blood of adult Drosophila melanogaster flies within two hours after inoculation, and is still detectable sixty days later (11). Investigation of this activity by isoelectric focusing reveals several blood proteins with antibacterial activity... 

Fly blood does not normally contain substances that kill bacteria, but flies inoculated with bacteria rapidly accumulate antibacterial proteins (ABs) in their blood. Wild type Drosophila have at least three different antibacterial proteins based on isoelectric points. Genetic variants identify structural genes for these antibacterial proteins. A DNA sequence that can encode a conserved portion of moth and fleshfly antibacterial proteins has been used to synthesize a complementary oligonucleotide probe. This probe recognizes a messenger RNA that appears in the fat body of Drosophila and Medflies only after they have been inoculated with bacteria. Bacteria-sensitive lethal mutations were induced to identify genes necessary for flies to survive a bacterial infection. 

Stock At contains only AB8.7 and AB9.1, while stock Am has only AB7.1. The wild stock Oregon R has all three spots. Stock Cu lacks all three antibacterial proteins found in wild type but has a novel band at pI7.6. In addition, stock Cu is quite sensitive to infection. We are currently mapping these mutations to identify the chromosomal location of genes that affect AB structure. 

The results of these experiments 1) provide genetic variants for genes that control the structure of antibacterial proteins 2) show that specific RNAs accumulate after a bacterial infection and 3)... 

Some of the ABs may have structural homology to antibacterial proteins isolated from the flesh fly (20,21) since an oligonucleotide probe that can encode a portion of the sarcotoxin protein recognizes an immune-specific RNA in Drosophila fat body cells, the cellular origin of Drosophila s ABs (unpubl.). The induction mechanism must work relatively rapidly since we found immune-specific RNA in fat body cells within 6 hours after inoculation. Because of its homology to sarcotoxin, we assume that the immune-specific transcript detected by the oligonucleotide probe encodes an antibacterial protein. 

Fujiwara S, imai J, Fujiwara M, Yaeshima T, Kawashima T, Kobayashi K. A potent antibacterial protein in royal jelly. Purification and determination of the primary structure of tayal-isin. J Biol Chem 1990 265 11333-11337. 

By virtue of their fused /3-lactam-thiazolidine ring structure, the penicillins behave as acylating agents of a reactivity comparable to carboxylic acid anhydrides (see Section 5.11.2.1). This reactivity is responsible for many of the properties of the penicillins, e.g. difficult isolation due to hydrolytic instability (B-49MI51102), antibacterial activity due to irreversible transpeptidase inhibition (Section 5.11.5.1), and antigen formation via reaction with protein molecules. 

The well-defined helical structure associated with appropriately substituted peptoid oligomers (Section 1.6) can be employed to fashion compounds that closely mimic the stracture and function of certain bioactive peptides. There are many examples of small helical peptides (<100 residues) whose mimicry by non-natural ohgomers could potentially yield valuable therapeutic and bioactive compounds. This section describes peptoids that have been rationaUy designed as mimics of antibacterial peptides, lung surfactant proteins, and coUagen proteins. Mimics of HIV-Tat protein, although relevant to this discussion, were described previously in this chapter (Sections 1.3.2 and 1.4.1). 

The proteins of the outer membrane, many of which traverse the whole structure, are currently the subject of active study. Some of the proteins consist of three subunits, and these units with a central space or pore running through them are known as porrns. They are thought to act as a mechanism of selectivity for the ingress or exclusion of metabolites and antibacterial agents (see Chapter 8). 

Linezohd (Zyvox) is an oxazolidinone, a tive-membered heterocychc ring that forms the core of the hnezohd structure. The approval of hnezohd by the FDA in 2000 marked the first new structural class of antibacterial introduced into medical practice in the United States in 40 years. It is notable for its activity against methicillin-resistant Staph aureus, MRSA, and vancomycin-resistant Enterococcus faecium, VRE. It is bacteriostatic rather than bactericidal but finds significant use in patients with an intact immune system. Like several other classes of antibacterials, linezolid is an inhibitor of protein synthesis. It interacts specifically with the RNA component of a bacterial ribosome subunit to prevent initiation of protein synthesis. 

Aminoglycoside a structurally complex antibacterial that works as bacterial protein synthesis inhibitor. 

Pharmacology Telithromycin belongs to the ketolide class of antibacterials and is structurally related to the macrolide family of antibiotics. Telithromycin blocks protein synthesis by binding to domains II and V of 23S rRNA of the 508 ribosomal subunit. Pharmacokinetics ... 

Figure 9.3 Targets for antibacterial drugs. The various classes of antibacterial drugs exert their effects at one of the four fundamental structural components of bacteria. Each of these components is vulnerable to drug attack. Penicillin, for example, attacks at the level of the cell wall chloramphenicol, however, works at the level of bacterial protein synthesis.

Their antibacterial and mutagenic activity is closely related to the reduction of the 5-nitro group, which is common to all nitroimidazole drugs, and the subsequent formation of reactive metabolites that bind to bacterial DNA, inhibiting DNA and protein synthesis in the microorganisms. Metabolism of 5-nitroimidaz-oles in mammals usually leads to covalently bound residues with a persistent imidazole structure. 

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