Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
  • C07F1/12—Gold compounds
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
  • A01N57/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having alternatively specified atoms bound to the phosphorus atom and not covered by a single one of groups A01N57/10, A01N57/18, A01N57/26, A01N57/34
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
  • A01N57/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having alternatively specified atoms bound to the phosphorus atom and not covered by a single one of groups A01N57/10, A01N57/18, A01N57/26, A01N57/34
  • A01N57/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having alternatively specified atoms bound to the phosphorus atom and not covered by a single one of groups A01N57/10, A01N57/18, A01N57/26, A01N57/34 containing heterocyclic radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/67—Phosphorus compounds having sulfur as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/54—Quaternary phosphonium compounds
  • C07F9/5463—Compounds of the type "quasi-phosphonium", e.g. (C)a-P-(Y)b wherein a+b=4, b>=1 and Y=heteroatom, generally N or O
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
  • C07F9/572—Five-membered rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
  • C07F9/576—Six-membered rings
  • C07F9/59—Hydrogenated pyridine rings

Definitions

• the present invention is directed, in general, to pharmaceutical compounds.
• the invention relates to a gold(lll) complex, having formula (I), to be used as antibacterial and/or antibiofilm agents.
• WHO has identified a group of multiresistant bacteria that are able to "escape" from the biocidal action of all known antibiotics and represent new paradigms in pathogenesis, transmission and resistance bacteria of particular concern include Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa (PAO) and Enterobacteriaceae species.
• Enterococcus faecium Staphylococcus aureus
• Klebsiella pneumoniae Klebsiella pneumoniae
• Acinetobacter baumannii Acinetobacter baumannii
• Pseudomonas aeruginosa Pseudomonas aeruginosa
• Gold(l) complexes have historically been studied as antimicrobial agents.
• a relevant example is the gold(l) complex auranofin, a drug initially approved as an antirheumatic agent, which also possesses potent antibacterial activity.
• organometallic cyclometalated gold compounds are their greater stability.
• Gold(lll) complexes tested for antimicrobial activity are either simple salts of Au(lll) (e.g., tetrachlorides, carboxylates, etc. Borhade, S, Int. Res. J. Pharm. 2012, 3, 189-
• An object of the present disclosure is to provide stable cyclometalated gold(lll) complexes having efficacy against a variety of microorganisms and low toxicity.
• a new therapeutic tool to treat the infections caused by these bacteria is provided.
• the compounds of formula (I) are not only highly active, as determined by in vitro tests, but are also highly stable under physiological conditions so they are expected to maintain their antibacterial activity in vivo in the same way. Additionally, in vitro and in vivo assays show low toxicity of the compounds of formula
• the present disclosure relates to a gold(lll) complex having formula (I):
• R 1 is independently selected from aryl and amine
• R 2 is independently selected from alkyl and cycloalkyl
• R 3 is independently selected from hydrogen, halogen, nitro, cyano, alkyl, alkyloxy, alkylamino, aminodialkyl, hydroxyalkyl, trialkylsilyl, aryldialkylsilyl, alkylthio, cycloalkyl, aryl, heterocycle, polycycle, amino acid, peptide and carbohydrate derivative; and
• R 4 is independently selected from alkyl, cycloalkyl, alkylalkoxy, alkylamino, dialkylamino, alkylthio, trialkylphosphino, dialkylarylphosphino, alkyldiarylphosphino, triaylphosphino, aryl, heterocycle, polycycle, amino acid, peptide and carbohydrate derivative.
• binuclear complexes analogous to (I) are included.
• a complex with two type (I) structures connected by a piperazine ring is used.
• homo and heterobinuclear complexes can be used. They include complexes prepared using a R 4 substitute that has coordination positions to another metal.
• radicals that can be used are:
• R 4 aliphatic amine such as NMe 2 , NEt 2 , N(CH 2 Ph) 2 , pyrrolidyl, piperidinyl, and azepanyl links, or heterocyclical including piperazinyl or morpholinyl; and
• ligand for dinuclear complexes for example piperazine, i.e. a homonuclear complex.
• Another aspect of the present invention relates to a conjugate comprising the cited gold(lll) complex of formula (I) and at least one carrier, preferably a pharmaceutical carrier.
• Another aspect of the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising the cited gold(lll) complex of formula (I) or the above-mention conjugate and at least one pharmaceutically acceptable excipient.
• the gold(lll) complex, the conjugate or the pharmaceutical composition is used in the manufacture of a medicament, for example for the treatment of a microbial infection.
• the gold(lll) complex, the conjugate or the pharmaceutical composition is used as a medicament in the treatment and/or prevention of bacterial infections caused by multiresistant bacteria or other microorganisms.
• the gold(lll) complex, the conjugate or the pharmaceutical composition is used to inhibit biofilm formation or development, to eliminate mature biofilms and/or to reduce the biofilm biomass.
• Another aspect of the present invention relates to a process for preparing the gold(lll) complex of formula (I), comprising reacting a compound of formula (V)
• X 1 is independently selected from halogen, hydroxide or acetoxy
• X 2 is independently selected from halogen, hydroxide or acetoxy
• R 1 is independently selected from aryl and amine
• R 2 is independently selected from alkyl and cycloalkyl
• R 3 is independently selected from hydrogen, halogen, nitro, cyano, alkyl, alkyloxy, alkylamino, aminodialkyl, hydroxyalkyl, trialkylsilyl, aryldialkylsilyl, alkylthio, cycloalkyl, aryl, heterocycle, polycycle, amino acid, peptide and carbohydrate derivative; and R 4 is independently selected from alkyl, cycloalkyl, alkylalkoxy, alkylamino, dialkylamino, alkylthio, trialkylphosphino, dialkylarylphosphino, alkyldiarylphosphino, triaylphosphino, aryl, heterocycle, polycycle, amino acid, peptide and carbohydrate derivative.
• Fig. 1 shows the structure of complex 2b
• Fig. 2 shows the structure of complex 2f
• Fig. 3 shows the structure of complex 2g
• Fig. 4 shows the structure of complex 2n
• Fig. 5 is a view of the molecular structure of complex 2g, with partial atom labelling scheme and displacement ellipsoids drawn at 50% probability level.
• Fig. 6 is a graph showing the toxicity of 2g.
• Fig. 7 is a 1 H-NMR spectrum of complex 2b
• Fig. 8 is a 13 C-NMR spectrum of complex 2b
• Fig. 9 is a 31 P-NMR spectrum of complex 2b
• Fig. 10 is a 1 H-NMR spectrum of complex 2g
• Fig. 1 1 is a 13 C-NMR spectrum of complex 2g
• Fig. 12 is a 31 P-NMR spectrum of complex 2g
• Fig. 13 is a 31 P -NMR spectrum of complex 2f in 0.25 ml_ CD 3 CN/0.25 ml_ of phosphate buffer, at 37 5 C, taken immediately after dissolution.
• Fig. 14 is a 31 P -NMR spectrum of complex 2f in 0.25 ml_ CD 3 CN/0.25 ml_ of phosphate buffer, at 37 5 C, taken 3 days after dissolution.
• Fig. 15 is a 31 P -NMR spectrum of complex 2f in 0.25 ml_ CD 3 CN and ISO culture broth in 0.25 ml_ of D 2 0.
• Fig. 16 is a 31 P -NMR spectrum of complex 2f in 0.25 ml_ CD 3 CN and 1 equiv. of glutathione in 0.25 ml_ of H 2 0.
• Fig. 17 is a 31 P -NMR spectrum of complex 2f in 0.25 ml_ CD 3 CN and 1 equiv. of ascorbic acid in 0.25 ml_ of H 2 0.
• Present invention relates in a first embodiment to a gold(lll) complex having formula (I):
• R 1 is independently selected from aryl and amine
• R 2 is independently selected from alkyl and cycloalkyl
• R 3 is independently selected from hydrogen, halogen, nitro, cyano, alkyl, alkyloxy, alkylamino, aminodialkyl, hydroxyalkyl, trialkylsilyl, aryldialkylsilyl, alkylthio, cycloalkyl, aryl, heterocycle, polycycle, amino acid, peptide and carbohydrate derivative
• R 4 is independently selected from alkyl, cycloalkyl, alkylalkoxy, alkylamino, dialkylamino, alkylthio, trialkylphosphino, dialkylarylphosphino, alkyldiarylphosphino, triaylphosphino, aryl, heterocycle, polycycle, amino acid, peptide and carbohydrate derivative.
• the compounds of formula (I) contain a positive charge and can form salts with organic or inorganic acids. Therefore, pharmaceutically acceptable salts of the compounds of formula (I) are also included within the scope of the invention. Any reference to a compound of formula (I) throughout the description includes a reference to any pharmaceutically acceptable salt of such compound of formula (I).
• pharmaceutically acceptable salts encompasses any salt without any limitation on the salt that can be used, provided that these are acceptable for administration to a patient.
• pharmaceutically acceptable salts include chloride, bromide, malonate, pyruvate, etc. Hexafluorophosphate is preferred.
• the invention relates to compounds of formula (I) having a minimum inhibitory concentration (MIC) of 0.125-0.5 mg/L for S. aureus, of 2-4 mg/L for S. maltophilia and of 1 -2 mg/L for H. influenziae, being lower than the MICs of other antibiotics used in the treatment infections caused by these microorganisms, as described in example 2 for S. aureus.
• MIC minimum inhibitory concentration
• present invention also provides a compound of formula (I) or any pharmaceutically acceptable salt for its use in the manufacture of a medicament for the treatment and/or prevention of a microbial infection.
• the present invention relates to the use of a compound of formula (I) as an antimicrobial agent for the treatment of a human or animal patient afflicted with an infection by multiresistant microorganisms, including the administration to said patient of an effective amount of a pharmaceutical composition containing the compound of formula (I).
• compounds of formula (I) have resulted in low-null toxicity in mice at doses greater than 5 mg/kg in weight, much higher than the concentration at which it is active.
• these compounds can be used in combination with other antimicrobials, typically broad spectrum antibiotics, to thereby enhance the antimicrobial efficacy of the therapy.
• Compounds of formula (I) can be combined with any type of antimicrobial agent used in therapy, as (but not limited to) vancomycin, daptomycin, fosfomycin, ciprofloxacin or imipenem.
• the combination of compounds of formula (I) with an additional antimicrobial agent can be achieved by administering both substances as a fixed dose combination in pharmaceutical dosage form or, alternatively, both drugs can be administered independently, according to a therapeutic combination regimen.
• the compound of formula (I) can be combined with another antibacterial agent by covalently bonding both compounds to form a single molecule.
• the compound of formula (I) can be linked to an antibacterial compound of fluoroquinolone, carbapenemic or penicillin derivative, according to formulas (ll-IV).
• biosynthetic pathways involved in the antibacterial activity of compound of formula (I) are studied. Their possible role in the interaction with intracellular proteins and enzymes, in the catalysation of various intracellular processes, in the ability of mutating the bacterial DNA and/or in the overexpression or repression of genes and the consequent proteins is studied using proteomics, genomics and microscopic approaches.
• present invention relates to a pharmaceutical composition comprising a compound of formula (I) and at least one acceptable pharmaceutical excipient or carrier.
• Another embodiment of the present invention relates to the use of the compounds of the present invention to inhibit the formation or development of biofilm, eliminating existent biofilms, and reducing the biofilm biomass.
• a method for inhibiting biofilm formation including exposing formed biofilms to an effective amount of the compound of the invention for eradication.
• compounds of formula (I) have minimal Biofilm Inhibition Concentrations (MBIC) lower than antibiotics used in the treatment of these infections as in the case of S. aureus.
• the compound of the invention is impregnated or deposited on the surface susceptible to biofilm formation.
• the surface can be the surface of a medical instrument such as: surgical equipment, implants or prostheses, catheters (urinary or venous), stents, pacemakers, dialysis equipment, heart valves and medical fixation instruments (plates, screws, nails ).
• a medical instrument such as: surgical equipment, implants or prostheses, catheters (urinary or venous), stents, pacemakers, dialysis equipment, heart valves and medical fixation instruments (plates, screws, nails ).
• Another embodiment of the present invention relates to a process for the preparation of a compound of formula (I) (as defined above) which comprises reacting a compound of formula (V)
• X 1 is independently selected from halogen, hydroxide or acetoxy
• X 2 is independently selected from halogen, hydroxide or acetoxy
• R 1 is independently selected from aryl and amine
• R 2 is independently selected from alkyl and cycloalkyl
• R 3 is independently selected from hydrogen, halogen, nitro, cyano, alkyl, alkoxyalkyl, aminoalkyl, aminodialkyl, hydroxyalkyl, trialkylsilyl, aryldialkylsilyl, alkylthio, cycloalkyl, aryl, heterocycle, polycycle, amino acid, peptide and carbohydrate derivative with a compound of formula (VI)
• R 4 is independently selected from alkyl, cycloalkyl, alkylalkoxy, alkylamino, dialkylamino, alkylthio, trialkylphosphino, dialkylarylphosphino, alkyldiarylphosphino, triaylphosphino, aryl, heterocycle, polycycle, amino acid, peptide and carbohydrate derivative, and subsequent formation of a pharmaceutically stable salt or solvate of the resulting complex by treatment with an organic or inorganic acid or their corresponding salts.
• the present invention also relates to a method for the preparation of compound V, consisting of the ortho-metallation of a thiophosphinic or thiophosphonic amide framework, followed by transmetallation with a gold(l) salt and oxidation to gold(lll), as represented in Scheme II:
• L is independently selected from a tertiary phosphine (Flower, KR, et al. Dalton Transactions 2010, 39, 3509-3520), a tertiary arsine (Pena-Lopez, M, et al Org. Biomol. Chem. 2012, 10, 1686-1694) or a thioether (Espinet, P, Organometallics, 2000, 19, 290-295).
• R 1 NEt 2
• N(R 2 ) 2 NEt 2
• R 3 H
• the oxidant agent is selected from X 2 (Viente, J, Areas, A, Marc, M, J. Organomet. Chem 1986, 309, 3689-378), PhlX 2 (Hofer, M., Gomez-Bengoa, E, Nevado, C, Organometallics 2014, 33, 1328-1332) or CF 3 I (Winston, MS, Wolf, WJ, Toste, FD, J. Am. Chem. Soc. 2014, 136, 7777-7782).
• complex (V) can be prepared by boron/Au(lll) metathetical reactions using the corresponding ortho borinated derivative of phosphinothioic amide VII (Price, GA, et al. Dalton Trans., 201 1 , 40, 1 1696-1 1697).
• the compounds of the present invention can be prepared by the methods described herein or small variations thereof, as well as by alternative methods.
• NMR spectra were obtained on a Bruker Avance III HD 300 ( 1 H 300.13 MHz; 13 C 75.47 MHz; 31 P 121 .49 MHz) and Bruker Avance III HD 500 ( 1 H 500.13 MHz; 13 C 125.76 MHz; 31 P 202.46 MHz). Chemical shifts are given in ppm using tetramethylsilane (TMS) for 1 H and 13 C as internal standards and 85% H 3 P0 4 for 31 P as external standard.
• TMS tetramethylsilane
• 1 H, 1 H ⁇ 31 P ⁇ and 31 P NMR spectra were acquired from all reaction crudes in CDCI 3 or CD 3 CN as solvent. The following abbreviations are used to indicate the multiplicity of signal: s - singlet, d - doublet, t - triplet, q - quartet and sep - septet.
• the auracyclic complexes 2 have also been characterized by electrospray ionization mass spectrometry (ESI-MS), showing a strong peak due to the gold cation. Calculated isotopic clusters were in excellent agreement with the experimental ones. Table 1 .-
• MRSA methicillin resistant S. aureus ; Cip, ciprofloxacin; Cli, clindamycin; Eri, erithromycin; Pen, penicillin; Lvx, levofloxacin; Gen, gentamicin.
• Cip ciprofloxacin
• Cli clindamycin
• Eri erithromycin
• Pen penicillin
• Lvx levofloxacin
• Gen gentamicin.
• Treatment Single intravenous dose (100 pL) of 2-10 mg/kg of the compounds 2 (or formula (I)) and vehicle control groups DMSO. Development: The animals were monitored for 2 weeks after the inoculation of the treatment. Signs of toxicity such as weight reduction, bristly coat, reduced mobility, ocular epiphora were verified. The animals were weighed each day until the end of the experiment. A decrease of 80% of the initial weight of the mouse was considered as an endpoint criterion. Result: No significant differences in weight were observed in the dose of 2 mg/kg of the molecule with respect to the control group, see Fig. 6. Example 4. Antibiofilm activity. -
• MRSA methicillin resistant S. aureus ; Cip, ciprofloxacin; Cli, clindamycin; Eri, erithromycin; Pen, penicillin; Lvx, levofloxacin; Gen, gentamicin.
• the proposed gold(lll) complex has also showed a synergistic effect with colistine.
• the minimal inhibitory concentrations of the combination of the gold(lll) complex and colistine in Gram-negative are significantly lower than those obtained with each antibiotic separately.
• the MIC of the gold(lll) complex for A. baumannii is 4 mg/L and the MIC for colistine is 64 mg/L.
• the MICs of each antibiotic decrease to 0.25 and 1 mg/L, respectively.
• a susceptible strain of MRSA was submitted to different concentrations of the gold(lll) complex during 30 days.
• the tube showing bacterial growth was spread into an agar plate and the colonies were tested for their resistance to the gold(lll) complex. Daptomycin was used as control of acquisition of resistance. The experiment was made by duplicate. After the 30 days, no increase in the MIC was found. Therefore, the gold(lll) complex does not generate resistance.
• mice infected but no-treated mice mice infected but no-treated mice
• mice treated with a single dose of 5 mg/kg mice treated with multiple doses of 5 mg/kg each 24h.
• the mice of the control group died after 48h post-inoculation.
• the mice of the single doses group died after 5 days post-inoculation.
• the mice of the multiple doses group died after 4 days post-inoculation.

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