Broad spectrum beta-lactamase inhibitors

1. A method of treating bacterial infection, the method comprising:

administering to an individual in need of treatment a therapeutically effective amount of a beta-lactam antibiotic;

wherein the beta-lactam antibiotic is also a beta-lactamase inhibitor that inhibits a beta-lactamase enzyme and

which comprises a leaving group that is in conjugation with the lactam nitrogen of the beta-lactam ring through a styryl moiety such that, when the beta-lactam ring is opened by the beta-lactamase enzyme to form a ring-opened compound, the leaving group is expelled to form a reactive moiety on the ring-opened compound, and the reactive moiety covalently binds to the beta-lactamase enzyme, wherein the reactive moiety is a substituted or unsubstituted cyclohexadienyl methide.

2. The method of claim 1 , wherein the styryl moiety has the structure:

wherein:

X is a leaving group;

the phenyl ring is cis or trans with respect to R 1 ;

R 1 and R 2 , are independently selected from the group consisting of hydrogen, halogen, (C1-C6) alkyl, (C1-C6) alkoxy and (C1-C6) thioalkyl; and

each R 8 and each R 10 is independently selected from hydrogen, halogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C7-C19) aralkyl, a 3-7-member-ring cyclic hydrocarbon, a 3-7 member heterocyclic, a (C6-C10) aromatic, a 6-10 member heterocyclic aromatic, a (C1-C6) alkoxy, a (C1-C6) thioalkyl, a —CO—R′, —CO 2 R′, —CO—N(R′) 2 , and —N(R′) 2 , wherein each R′ is independently selected from hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C7-C19) aralkyl, a 3-7-member-ring cyclic hydrocarbon, a 3-7 member heterocyclic, a (C6-C10) aromatic and a 6-10 member heterocyclic aromatic group, and wherein each of said groups is optionally substituted.

3. The method of claim 2 , wherein R 1 and R 2 are both hydrogen.

4. The method of claim 2 , wherein R 8 and R 10 are independently selected from hydrogen, halogen, (C1-C6) alkyl, and (C1-C6) alkoxy.

5. The method of claim 1 , wherein the styryl moiety has the structure:

wherein X is a leaving group.

6. The method of claim 1 , wherein the cyclohexadienyl methide has the structure:

wherein:

R 2 is selected from the group consisting of hydrogen, halogen, (C1-C6) alkyl, (C1-C6) alkoxy and (C1-C6) thioalkyl; and

each R 8 and R 10 is independently selected from hydrogen, halogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C7-C19) aralkyl, a 3-7-member-ring cyclic hydrocarbon, a 3-7 member heterocyclic, a (C6-C10) aromatic, a 6-10 member heterocyclic aromatic, a (C1-C6) alkoxy, a (C1-C6) thioalkyl, a —CO—R′, —CO 2 R′, —CO—N(R′) 2 ; and —N(R′) 2 , wherein each R′ is independently selected from hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C7-C19) aralkyl, a 3-7-member-ring cyclic hydrocarbon, a 3-7 member heterocyclic, a (C6-C10) aromatic and a 6-10 member heterocyclic aromatic group, wherein each of said groups is optionally substituted.

7. The method of claim 6 , wherein R 2 is hydrogen.

8. The method of claim 6 , wherein R 8 and R 10 are independently selected from hydrogen, halogen, (C1-C6) alkyl, and (C1-C6) alkoxy.

9. The method of claim 1 , wherein the cyclohexadienyl methide has structure:

10. The method of claim 9 , wherein the styryl moiety has the structure:

wherein X is a leaving group.

11. The method of claim 1 , wherein the beta-lactam antibiotic is a cephalosporin, a carbapenem or a monobactam.

12. The beta-lactam antibiotic of claim 1 , wherein the beta-lactam antibiotic is a cephalosporin.

13. The method of claim 1 , wherein the individual in need of treatment is an individual suffering from an infection caused by an antibiotic resistant bacteria.

14. The method of claim 1 , wherein the individual in need of treatment is an individual suffering from an infection caused by a Gram-negative bacterium.

15. The method of claim 14 , wherein the Gram-negative bacterium is selected from the group consisting of Escherichia coli 0157:H7; Salmonella enterica; Salmonella typhi; Shigella dysenteriae; Yersinia pestis; Pseudomonas aeruginosa; Vibrio cholerae; Bordetella pertussis; Haemophilus influenzae; Helicobacter pylori; Helicobacter felis; Campylobacter jejuni; Neisseria gonorrhoeae; Neisseria meningitides; Brucella abortus ; and Bacteroides fragilis.

16. The method of claim 1 , wherein the individual in need of treatment is an individual suffering from an infection caused by a Gram-positive bacterium.

17. The method of claim 16 , wherein the Gram-positive bacterium is a bacterium selected from the group consisting of: methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible Staphylococcus aureus (MSSA), glycopeptide intermediate-susceptible Staphylococcus aureus (GISA), methicillin-resistant Staphylococcus epidermitis (MRSE), methicillin-sensitive Staphylococcus epidermitis (MSSE), vancomycin-sensitive Enterococcus faecalis (EFSVS), vancomycin-sensitive Enterococcus faecium (EFMVS), penicillin-resistant Streptococcus pneumoniae (PRSP), and Streptococcus pyogenes.

18. The method of claim 1 , wherein said beta-lactam antibiotic also acts as a beta-lactamase inhibitor by irreversibly binding to a beta-lactamase enzyme.

19. The method of claim 1 , wherein the leaving group is selected from the group consisting of: halide, pyridinium, thiol, —SC(O)R′, —OCOR′, sulfenyl, phenoxy, pentafluorphenoxy, and tosyl, and wherein R′ is selected from optionally substituted alkyl and optionally substituted aryl groups.

20. The beta-lactam antibiotic of claim 1 , wherein the leaving group is a halide or a pyridinium.

21. The beta-lactam antibiotic of claim 1 , wherein:

the beta-lactam antibiotic is a cephalosporin;

the styryl moiety has the structure:

wherein X is a leaving group; and

the cyclohexadienyl methide has structure: