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US 20100028334A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0028334 A1 Cottarel et al. (43) Pub. Date: Feb. 4, 2010 (54) COMPOSITIONS AND METHODS TO Publication Classification POTENTIATE COLISTIN ACTIVITY (51) Int. Cl. A638/12 (2006.01) (75) Inventors: Guillaume Cottarel, Mountain AOIN 37/00 (2006.01) View, CA (US); Jamey A 6LX 39/395 (2006.01) Wierzbowski, Stoneham, MA (US) A6IP3L/04 (2006.01) Correspondence Address: CI2O I/68 (2006.01) RONALDI. EISENSTEIN (52) U.S. Cl. ................... 424/130.1: 514/2: 514/9: 435/6 100 SUMMER STREET, NIXON PEABODY LLP BOSTON, MA 02110 (US) (57) ABSTRACT A pharmaceutical composition comprising an antimicrobial (73) Assignee: TRUSTEES OF BOSTON agent and an enhancer of an antimicrobial agent, wherein the UNIVERSITY, Boston, MA (US) enhancer of an antimicrobial agent is an inhibitor of gene, that by inactivating the gene product potentiates the effectiveness (21) Appl. No.: 12/519,336 of the antimicrobial agent. In some embodiments, the phar maceutical composition further comprises a pharmaceuti (22) PCT Filed: Dec. 13, 2007 cally acceptable carrier. In some embodiments, the antimi crobial agent is an antimicrobial peptide Such as a polymyxin, (86). PCT No.: PCT/US07/87397 for example but not limited to colistin. In some embodiments of the present invention provides methods to treat and/or S371 (c)(1), prevent infection of a Subject with a microorganism by (2), (4) Date: Jun. 15, 2009 administering a pharmaceutical composition comprising an antimicrobial agent and an enhancer of an antimicrobial Related U.S. Application Data agent. In some embodiments, the present invention provides (60) Provisional application No. 60/875,003, filed on Dec. methods to inhibit growth of a microorganism by administer 15, 2006, provisional application No. 60/963,265, ing a pharmaceutical composition comprising an antimicro filed on Aug. 3, 2007. bial agent and an enhancer of an antimicrobial agent. Overnight culture in LB from a previous onvernight incubation in presence of Kanamycin Transfer 30 into 30 us Transfer 30 ul into 30 ul LB Containing Colistin Stamp onto LB agar plate e-plates analysis List of mutants with overlapping score Patent Application Publication Feb. 4, 2010 Sheet 1 of 5 US 2010/0028334 A1 ?eun61-I Patent Application Publication Feb. 4, 2010 Sheet 2 of 5 US 2010/0028334 A1 ºwnisse,ogu ,^eunders mr zeun61 Patent Application Publication Feb. 4, 2010 Sheet 3 of 5 US 2010/0028334 A1 penueSuOO penuesuoo-uoN - ". --- unpued 1 sisuaapeup S sleuoyaejo apoptinct S. Jehog spsad aelajoyoA 4d6s aeuauasips esoufinjeed spp.5uyuau N eaeoquiou of N eydouneud gold H s aezuanyuh 4. 103 aeasuag sauafo AdS S2 equounaud's spuapida's snaines sisoolah saulafioA)ououjuepio spynsg snaiaag t spejtpueg 3 9iš:is c. 555= i:. .-Jos?::::iii;ski; ( : 222: ;K ; ;- ;28 ; , a 52.222;Es qualiiiii lic is g; isitc is 32:::::::::- 5:55:iiiir ; ; isg:; ; ; ; is Patent Application Publication Feb. 4, 2010 Sheet 4 of 5 US 2010/0028334 A1 O D N O CN O)G is O) o c O g Sn () O O CD O O W. D. o As O O O t E O. F CD s E t O O. -9 s e N NC D r CY) CN ves i U 3 S O. O J O O W Patent Application Publication Feb. 4, 2010 Sheet 5 of 5 US 2010/0028334 A1 -- --- s | 3 o {e o Y{ o &. &. ; st is 33 8 8 8 5 . : le US 2010/0028334 A1 Feb. 4, 2010 COMPOSITIONS AND METHODS TO ions, it destabilizes the wall and can insinuate into it. It per POTENTIATE COLISTIN ACTIVITY forates the cell wall, causing distortion of this structure and the release of intracellular constituents in the outside. Colistin FIELD OF THE INVENTION appears to re-emerge as recent clinical findings have been published, focusing on evaluation of efficacy, emerging resis 0001. The present invention relates generally to methods tance and potential toxicities. The use of colistin at current and compositions to treat drug resistant bacteria, and more therapeutic effective doses is often associated with neurotox particularly to methods and compositions to potentate the icity and nephrotoxicity. Therefore it would be desirable to activity of lipopeptides. reduce the toxicity of colistin. 0007. Therefore, there is great need in the art to for an BACKGROUND OF THE INVENTION effective therapy against multi-drug resistant microorgan 0002 Increasing multidrug resistance in Gram-negative isms, in particular gram-negative bacteria and multi-drug bacteria, in particular Pseudomonas aeruginosa, Acineto resistant gram-negative bacteria, for example, polymyxin bacter baumannii, and Klebsiella pneumoniae, presents a resistant gram-negative bacteria Such as P. aeruginosa and A. critical problem. Limited therapeutic options have forced baumannii, or to increase the sensitivity of microorganisms to infectious disease clinicians and microbiologists to reap treatment. praise the clinical application of colistin, a polymyxin anti biotic discovered more than 50 years ago. Colistin is now one SUMMARY OF THE INVENTION of the last drug resorts to fight Gram-negative bacteria. 0008. The present invention relates to methods and com 0003. The world is facing an enormous and growing threat positions to potentate the efficacy of antimicrobial agents, for from the emergence of microorganisms that are resistant to a example antimicrobial peptides. The inventors have discov wide range of currently available antibiotics. For example, ered that by inactivating certain genes, the effectiveness of infections caused by utility drug resistant gram-negative bac antimicrobial agents, such as antimicrobial peptides is teria, particularly Pseudomonas aeruginosa and Acineto increased. Accordingly, the present invention relates to bacter baumannii, are becoming a critical challenge in com inhibitors of such genes as enhancers of antimicrobial agents. promised hospital patients (e.g. patients in intensive care In alternative embodiments, the present invention relates to a unite, patients with cystic fibrosis or diffuse panbroncholitis), composition comprising one or more antimicrobial agents and with seemingly trivial infections in sites Such as middle with one or more enhancers of antimicrobial agents. and central ear and eyes. The level of resistance to front line 0009. As disclosed herein, the inventors have discovered a anti-pseudomonal agents is alarmingly high. Of particular method of reducing the toxicity of antimicrobial agents. Such concern are reports on antibiograms of P aeruginosa and A. as for example, Colistin by co-administering an enhancer of baumannii in hospital outbreaks, where colistin, a member of the antimicrobial agent, for example an inhibitor of the gene the polymyxin class of antibiotics, is the only effective anti products as disclosed herein in Table 4 or Table 2. biotic. Unfortunately, polymyxin-resistant P aeruginosa has 0010. Using a functional genomics approach, the inven been isolated from patients with eye infections, ear infec tors discovered that inactivation of specific gene products tions, and particularly in the sputum of patients with cystic render the bacteria more susceptible to colistin, a potent but fibrosis. The appearance of polymyxin-resistant gram-nega toxic antibiotic. For example, the inventors demonstrate that tive pathogens is of great concern. deletion of the ubiFH and iscS loci render the bacterial cells 0004 Colistin is a polymyxin antibiotic produced by cer more sensitive to colistin. The inventors also demonstrate that tain strains of Bacillus polymyxa. Colistin is effective against that potassium tellurite, an inhibitor of IscS, potentiates colis Gram negative bacilli, except Proteus and Burkholderia tin efficacy. Accordingly, the inventors have discovered dif cepacia and is particularly effective against multi-drug resis ferent combination therapies with colistin, and their use with tantisolates of Pseudomonas aeruginosa, Acinetobacter bau a wide variety of major classes of antibiotics. mannii and Klebsiella pneumoniae. Colistin interacts with 0011. Another aspect of the present invention relates to the bacterial cytoplasmic membrane, changing its permeabil methods to screen for gene products, which when inactivated, ity therefore causing leakage of the cell contents. potentiate the effect of antimicrobial agents, such as antimi 0005. However, despite the ability of colistin to kill multi crobial peptides. Another aspect of the invention relates to drug resistant bacteria, its use in treating patients is highly identification of inhibitors of such genes, and thus identifica limited by the fact that it is highly neurotoxic and nephrotoxic tion of enhancers of antimicrobial agents, such as antimicro and results in adverse renal effects. Colistin must be admin bial peptides. Another aspect of the present invention relates istered parenterally as it is not absorbed by the gastrointesti to a pharmaceutical formulation comprising a composition of nal tract, mucous membranes or intacted or denuded skin. at least one antimicrobial agent, such as an antimicrobial Colistin administration, particularly intravenously, was aban peptide, and at least one enhancer to the antimicrobial agent. doned due to a high incidence of nephrotoxicity and neuro In such an embodiment, the enhancer of the antimicrobial toxicity. In regard of the emergence of bacteria resistant to agent is an inhibitor of a gene product, which by inactivating major classes of antibiotics and of the lack of new classes of the gene product potentiates the effectiveness of the antimi antibiotics, colistin is re-appearing as a valuable antibacterial crobial agent. For example, the
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