finity) to human ribosomal RNA, causing serious side effects such as deafness and kidney damage. "An important objective in designing A group of Californiaresearchershas deter- modified aminoglycosides is to make them mined the structure of a complex formed more potent against bacteria but less poby an aminoglycoside antibiotic and bacteri- tent against eukaryotic cells," says microbiology professor Julian Davies of the Unial ribosomal RNA. The structure, obtained in solution by versity of British Columbia, Vancouver, nuclear magnetic resonance spectroscopy, who specializes in aminoglycoside antibishows how this class of drugs works and otics and antibioticresistance.With a clear may lead to development of agents that model of aminoglycoside-RNA binding are less toxic and less prone to antibiotic now in hand, this goal has become much more accessible, he notes. resistance than current aminoglycosides. Although the Santa Cruz group's strucThe determination of the structure is the fruit of more than two years of effort ture is that of a complex of paromomycin, it also is applicable to other aminoglycosides—such as gentamicin, which is more widely used—because the drugs in this class have common structural features and interact with ribosomal RNA in a similar manner. Puglisi and coworkers have sought the structures of several other aminoglycosides bound to ribosomal RNA, but the quality of the data was best with paromomycin. The structure indicates that the presence of the antibiotic may inhibit normal dissociation of aminoacyl transfer RNA from the ribosome during protein synthesis, causing the ribosome to make more errors in translating the genetic code. The structure also demonstrates how antibiotic resistance Model shows antibiotic paromomycin (yellow) complexed can arise, and it provides a with bacterial ribosomal RNA. RNA backbone is red, structural basis for known binding pocket into which antibiotic fits is blue, and the rest ofRNA is green. Uridine-1406, adenine-1493, and differences in the affinity uridlne-1495 are key nucleotides In RNA chain. with which the aminoglycosides bind to bacterial RNA by postdoctoral researcher Dominique and human ribosomal RNA. Puglisi believes the data can be used to Fourmy, graduate student Michael I. Recht, technician Scott C. Blanchard, and bio- create aminoglycoside drugs with better chemistry professor Joseph D. Puglisi of efficacy and lower toxicity. "Their toxicity the University of California, Santa Cruz is due to their poor discrimination between bacterial and human targets," he [Science, 274,1367 (1996)]. The structure shows the aminoglyco- says. "We feel we can improve that disside antibiotic paromomycin bound to a crimination, based on the structure." He 27-nucleotide piece of bacterial ribosom- points out that others are also trying to deal RNA. Aminoglycosides such as paro- velop improved aminoglycosides—such as momycin bind irreversibly to 30S ribo- chemistry professor Chi-Huey Wong and somal RNA, a key part of the protein- coworkers at Scripps Research Institute, making machinery of the cell, and thus who recently reported on the combinatoinhibit bacterial protein synthesis. But rial synthesis of aminoglycoside antibiotic the drugs' precise mechanism of action mimetics [/. Am. Chem. Soc, 118, 10150 has not been known. The aminoglyco- (1996)]. sides also bind (although with lower afStu Borman
Structure opens way to improved antibiotics
Shareholder seeks sale or merger of Petrolite In an effort to maximize stockholders' value, Petrolite's largest shareholder has drafted a plan to revamp the board of directors of the St. Louis-based specialty chemical maker, forming a board that will pursue negotiations to sell or merge the company with another firm. According tofilingswith the Securities & Exchange Commission on Nov. 12, William S. Barnickel & Co., an asset management firm based in St. Louis, is calling for shareholders to vote out five of Petrolite's 10 board members—including Paul H. Hatfield, chairman, president, and chief executive officer. Barnickel owns 5.3 million Petrolite shares, more than 47% of the outstanding shares. Barnickel proposes five replacement directors who "intend to analyze the financial and operating status of the company and, if deemed to be in the best interests of the company's stockholders, to pursue a process for the sale or merger of the company on the most advantageous terms for all stockholders." Also on Nov. 12, Barnickel filed a complaint in the Delaware Court of Chancery against Petrolite's shareholders' rights agreement or "poison pill." That agreement would trigger preventive actions against a possible Barnickel ally or other entity that acquires a stake of 15% or more in Petrolite, if it does not first receive approval from Petrolite's board. Barnickel is grandfathered from the poison pill. Petrolite responded to Barnickel's action on Nov. 15. A statement by a special committee of independent directors calls on Petrolite's management and financial advisers "to explore a possible business combination with third parties to deter-
Petrolite at a glance viU* $365 million infiscal1995a i
. m . ^ $15.2 million in fiscal
1995a,b
in USIIUJ it ;s St Louis
» i'.'pi«-x— 1,800worldwide r.u•••"« < Oil-field and industrial chemicals, specialty polymers and waxes, and chemical process equipment and related services a Fiscal year ending Oct. 31, 1995. b Excluding charge for asset write-down.
NOVEMBER 25, 1996 C&EN 11
