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New Cetus Antibiotic p activity designed to discover new antibiotics. For the most part, this Most major pharmaceutical companies presently carry out some form of a number of totally different biological strategies to uncover new types from soil samples, to find new antibiotic activity. Cetus has developed 4, of antibiotic activity. We believe that each of our approaches is l high. 40 '( a ewr' s i - q.; the likelihood of having found a new and novel type ofvcompound is very nature of our approach, should we find any antibiotic activity at all, nove , biologically sound and relatively easy to carry out. Due to the a, . Q~- . 1 .,.j•, ., ~L• examples of such protocols are outlined belowh ,` Z-ti~~ ,x r :z~~ ''~as r `:t. ~W , j...r.? ~ Biological Incorporation of Critical Precursor Mdlecules.?I'~' possible that some of'the mutants will biochemically incorporate broths of a large.'numbe"r of mutant microorganisms it is quite compounds. one,addscdiaminobutyric acid to the fermentation specifically impart.th anti-gram negative activity to these gram negative activity and'it is the diaminobutyric acid that seems ;,. o integral part of Gt~iese1`antibiotics. They both possess good anti and colistin. Dzaminobutyricacid is an amino acid that forms an Specific examples of~~this~phenomenon are the antibiotics polymixin~ and the "toxic segmen~ of the molecule" are separate and distinct.'.`; limit their usefulness.Q~The "antibiotic segment of the molecule" though these antibiotics have potent antimicrobial activity, they also have serious shortcomings,-such as toxicity that seriously part of several classes of antibiotics. Cenerally speaking, al-'.- ^ It is known that certain chemical moieties cons~itute an integral useful antibiotics'with anti-gram negative activity. ..:; aminobyturs.G, acid into totally new molecules yielding novel and ChalLenging;Microorganisms with Hormones from Higher Animals. ~ " b o G, g animala`"such as mammals are chemicals totally foreign to microor- Cetus~'investigators have shown that although hormones from hi her .ganisznsnonetheless they exert a profound effect on the internal, chemisfry of the microorganism. It is possible that traditional cortisone dramatically alters the way in which microorganisms . metabolize amino acids and synthesize carotenoids. Since these likely to be new and novel. For example, we have shown that hydro-,' these new chemicals have antibiotic activity that activity is ordinarily produced in their "natural metabolic state." If any of., of mammalian hormones would produce a large number of chemicals not antibiotic-producing microorganisms fermenting under the influence I activities are important in the production of known antibiotics, might not the altered state produce totally new compounds? , i ~ sc?..:y aa~ . r ~i. ~~r :.t, c:(c:i:tS+s , ; > u.i ~ ~:.`.'.`<x a?w K~..:~:.•

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Mutating Microorganisms Known to be Non-Producers of Antibiotics. ,;. :,: Using Microorganisms to Modify Known Significant Antibioticy.s or Their Precursors. Many microorganisms are known that do not produce antibiotics of . any type. Yet these organisms possess a complex internal chemistry that, if altered by mutation, might conceivably produce antibiotic activity. The Cetus technology would allow us to mutate large numbers of such organisms, searching for evidence of any antibiotic activity. The appealing aspect of this approach is that, because of the expected low incidence of positives, very large numbers_of'.; mutants can be screened quite easily. Here again, the potential for novelty is high. `.-r' . _ i `.n .:r.,;.' c.. . ^Ci. - r. .., . .•' r.~-fp"'Si''~t ,t',''r4 ° . .,'~ .~. a <~ precursors of compounds presently exhibiting-large m arket share or exciting potential. Microbiological moc~.ficationr& pharmaceutica z ¢ l Si ' '•r:. 'a,. r~ ~,.'~ ~IC Z y i l ~ ,`~ ~X'!. ~ K .. , Perhaps the most attractive proposal at Cetus,;kox generating new,;t~;r antibiotics with a high likelihood of immediate~thera%utic and market appeal involves biological modifica,~ionf'of com~ounds o ~ compounds produced elsewhere has,'~-avlrea&y~een expioited, e.g. in ~j_:,~ the steroid field. One specific examplef: We beiieve that our approach has a high probabilify of success irrjaddressing situations in which effectiveness andS~.abili~requirev~separate changes such as may be the case with Merck' s:new; much-publicized thienamycin. 4` ~fi O~ sSti~ - . `. -'i• ,',_I a o~~z ° G ti~, o~' o 04{ fi a~ fi ~~ ~ , GO ~ti • . G~ Qc` oofi :K*h,14i :z- s`tj tr~ ra-s.,..r ~ .1 u.~.._. z~` ~ A'r'~ ~ ~j c ~A~~~~"~}t l• " f. ~. . ,~ . , ~ . . ' I ; ~ ' • ~ n~ ., ';. t . , ...tzi. . 1 <,t., '~: ;-fi.'~.`'~c3i11r...~ . s . . - .. .. . . , . ., . . . . . . . .. . . . . . . _ . . , . . . -::k 1.- £~' _ .,s ..

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