An Investigation of Antibiotic g Derivatives to Overcome Resistance Ji Jim Birrell i ll Ezgi Hacisuleyman Ting Huang Daniel Johnson Zhiyong Poon Susan Zawaski December 4 th , 2008
Agenda Agenda • Background of antibiotic resistance Background of antibiotic resistance • Overview of antibiotic derivatives • Derivative examples • Derivative examples – Vancomycin – Tetraphase: a start ‐ up developing new derivatives Tetraphase a start up developing new derivatives • Current status in large pharma • Alternatives for overcoming antibiotic resistance l f b • Conclusion
Antibiotic resistance Antibiotic resistance “The ability of bacteria or other microbes to resist The ability of bacteria or other microbes to resist the effects of an antibiotic. Antibiotic resistance occurs when bacteria change in some way that reduces or eliminates the effectiveness of drugs, chemicals, or other agents designed to cure or prevent infections. The bacteria survive and continue t i f ti Th b t i i d ti to multiply causing more harm.” ‐ CDC
Causes of resistance Causes of resistance Several factors contribute to development of antibiotic resistance: i • Patients improperly self ‐ medicating • Patients not complying with medication guidelines a e s o co p y g ed ca o gu de es • Health professionals improperly prescribing antibiotics • Over ‐ the ‐ counter availability of antibiotics • Cross resistance due to antibiotic use in animal husbandry • Cross ‐ resistance due to antibiotic use in animal husbandry • Thus bacteria have rapidly evolved to acquire Thus bacteria have rapidly evolved to acquire resistance to multiple drugs • In addition very few new antibiotics introduced to clinical use over past decades
How resistance occurs How resistance occurs D Drug inactivation or i ti ti • modification Alteration of target site Alteration of target site • Alteration of metabolic • pathway Reduced drug • accumulation (decreased permeability ( p y or increased active efflux) http://www.scq.ubc.ca/wp ‐ content/uploads/2006/08/ResistanceMechanisms.gif
Overview of antibiotic derivatives Overview of antibiotic derivatives • Antibiotic derivatives are synthetic analog libraries of Antibiotic derivatives are synthetic analog libraries of existing antibiotics created through chemical/biological processes • New derivatives are screened for improved efficacies against bacterial infections Producing derivatives: • Reducing carboxyl groups • Carbohydrate modification • Ring addition Ring addition • Structural change and different stereoisomers
Examples of derivatives Examples of derivatives • Vancomycin: – Initially developed to treat penicillin ‐ resistant Staphylococcus aureus – Since been employed as a final option for curing other resistant infections infections – Emergence of Vancomycin ‐ resistant bacterial strains poses a serious problem • Derivatives: – Modified with a series of hydrophobic subunits and these derivatives have been shown to be active against Vancomycin derivatives have been shown to be active against Vancomycin ‐ resistant bacteria strains – However, the derivatives increase the hydrophobicity and impart unfavorable pharmacokinetics to the molecule impart unfavorable pharmacokinetics to the molecule
Examples of derivatives Examples of derivatives • Tetracyclines: – Class of molecules characterized by four fused rings – First compound isolated was chlorotetracycline in 1948 – Soon discovered that many compounds in this class showed – Soon discovered that many compounds in this class showed excellent activity against a wide range of bacterial strains, leading to the commercialization of doxycycline by Pfizer in 1967 and minocycline by Lederle in 1972 – A number of analogues of tetracycline are still used today – Due to the wide use of tetracyclines across a number of decades, a large bacterial resistance has built up decades, a large bacterial resistance has built up
Tetracycline derivatives Tetracycline derivatives • Derivatives: – In 2005, Professor Andrew Myers of Harvard reported a simple, convergent synthesis of a number of the tetracyclines – Much of the functionality on the lower part of the A, B, and C rings is used to bind to the bacterial ribosome, which is crucial i i d t bi d t th b t i l ib hi h i i l to its function. – The D ring is the spot on the molecule where functionalization would be most effective, and Myers’ synthesis takes advantage o ld be most effecti e and M ers’ s nthesis takes ad antage of this by allowing a preformed D ring to be coupled to a fixed AB ring – This strategy is extremely useful for generating a wide number This strategy is extremely useful for generating a wide number of analogues of tetracyclines
Myers derivative example Myers derivative example
Tetraphase: a start ‐ up developing new derivatives Tetraphase: a start up developing new derivatives • Due to the promise of this new synthetic route, Tetraphase Pharmaceuticals was created in 2006 with the goal of commercializing new drugs to combat bacterial resistance b t b t i l i t • Tetraphase received $25 million in class A funding from a combination of five different venture capital from a combination of five different venture capital firms Demonstrates the market need for new antibiotics and the great promise of the technology technology
Current status in large pharma • According to some, the source of new antibiotics is unlikely to come from combinatorial libraries – No significant increase in new structural leads – The first generation synthetic libraries in the early to mid ‐ 1990s provided quantity but not quality provided quantity but not quality • Many companies have run their compound libraries on promising targets without success and have left the p g g antibacterial therapeutic area • GSK and Pfizer have antibiotic products in Phase I
Alternatives for overcoming resistance Alternatives for overcoming resistance Enacting stricter regulation of antibiotic use act g st cte egu at o o a t b ot c use Preserving existing antibiotics for as long as possible by reducing inappropriate antimicrobial Shift from broad to more targeted treatments Develop combination treatments Combination therapy with two or more antibiotics is used in special cases: – To prevent the emergence of resistant strains – To treat emergency cases – To take advantage of antibiotic synergism (when the effects of a combination of antibiotics is greater than the sum of the effects of the individual antibiotics) individual antibiotics)
Alternatives for overcoming resistance Alternatives for overcoming resistance Search for new antibiotics Synthesis of new chemical entities Synthesis of new chemical entities • • Screening NCEs for new antibiotics • Researchers have been screening natural sources (e.g., soil bacteria, extracts from plants – and fungi from unusual locations) to attempt to isolate new antibiotics Mammalian peptide antibiotics M li tid tibi ti • Insects, frogs and humans all secrete peptides that exhibit antimicrobial activity at their – mucosal and epithelial surfaces. A number of groups are exploring the possibilities of adapting them to produce new, more potent antibiotic peptides Revitalizing old antibiotics Altered peptide synthetases • Phenotypic conversion Phenotypic conversion • • An alternative approach to revitalizing old antibiotics is to directly inhibit the resistance – mechanism employed by the bacterium, thus allowing the antibiotic to work again. This is known as phenotypic conversion.
New molecular targets for antibiotics Principal targets for antibiotic action : metabolic pathways in bacteria that have been, or are proposed to be, targets for antibiotic action a | Cell ‐ wall biosynthesis b | Protein biosynthesis c | DNA and RNA replication d | Folate metabolism d | Folate metabolism e | Cell surface decoration f | Isoprenoid biosynthesis e | Cell ‐ surface decoration f | Isoprenoid biosynthesis
Conclusion Conclusion � Despite a call for minimizing unnecessary antibiotic prescribing and media attention on the spread of MRSA, established antibiotic resistance is proving hard to displace hard to displace � New resistances continue to emerge and to proliferate at new sites at new sites � Thus there is a strong need for new antibiotics � Antibiotic derivatives seem to be a promising solution, � A ibi i d i i b i i l i but far greater efforts (at all levels: large pharma, start ups, and in academic research labs) are needed to ups, and in academic research labs) are needed to overcome this great threat
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