Bicyclic aryl monobactam compounds and methods of use thereof for the treatment of bacterial infections

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

W is a bond or O;

R X and R Z are independently hydrogen, —SC 1 -C 3 alkyl, C 1 -C 3 alkyl, —(C 1 -C 3 alkylene) n OC 1 -C 3 alkyl, or —(C 1 -C 3 alkylene) n NC 1 -C 3 alkyl, wherein said —SC 1 -C 3 alkyl, C 1 -C 3 alkyl, —(C 1 -C 3 alkylene) n OC 1 -C 3 alkyl and —(C 1 -C 3 alkylene) n NC 1 -C 3 alkyl are optionally substituted with one to seven fluorines;

or, alternatively, R X and R Z , together with the carbon to which they are attached, form a monocyclic C 4 -C 7 cycloalkyl or a monocyclic C 4 -C 7 heterocycloalkyl with 1, 2, or 3 heteroatom ring atoms independently selected from N, O and S, wherein said C 4 -C 7 cycloalkyl and C 4 -C 7 heterocycloalkyl are optionally substituted with one to three substituents independently selected from —F, —OH and —OC 1 -C 3 alkyl;

X is N or CR 1 ;

R 1 is hydrogen, C 1 -C 3 alkyl, or halogen; wherein said C 1 -C 3 alkyl is optionally substituted with one to three R a ;

each occurrence of R a is independently hydrogen, halogen, C 1 -C 3 alkyl, —NR c R d , —OR e , or —C(O)NR c R d ;

Z is C 1 -C 3 alkylene, optionally substituted with one to three R b ;

each occurrence of R b is independently —C 1 -C 6 alkyl, —C 3 -C 7 cycloalkyl, —C(O)OR e , —C(O)NR c R d , tetrazolyl, oxadiazolonyl, HetA, AryA, —S(O) m R e , —S(O) m NR c R d , or P(O)(R e ) p wherein said —C 1 -C 6 alkyl and —C 3 -C 7 cycloalkyl are optionally substituted with one to three R a and wherein said AryA and HetA are optionally substituted with one to four R 4 ;

AryA is a 5- or 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S;

HetA is a 4- to 6-membered saturated or monounsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, NH, N as a quaternary salt, O and S;

Y is a bond, O, NR 2 , S, or CH 2 ;

R 2 is hydrogen, —C 1 -C 3 alkyl, —C(O)R e , —C(O)NR c R d , —S(O) m R e , or —S(O) m NR c R d , wherein said —C 1 -C 3 alkyl is optionally substituted with one to three R a ;

A 1 is a 9- to 11-membered bicyclic aromatic ring with 0, 1, 2, 3, or 4 heteroatom ring atoms independently selected from N, NH, N as a quaternary salt, O and S, optionally substituted with one to four R 4 ;

each occurrence of R 4 is independently:

(a) —C 1 -C 6 alkyl,

(b) —C 2 -C 6 alkenyl,

(c) —C 2 -C 6 alkynyl,

(d) halogen,

(e) —OR e ,

(f) —S(O) m R e ,

(g) —S(O) m NR c R d ,

(h) —C(O)R e ,

(i) —OC(O)R e ,

(j) —C(O)OR e ,

(k) —CN,

(l) —C(O)NR c R d ,

(m) —NR c R d ,

(n) —NR c C(O)R e ,

(o) —NR c C(O)OR e ,

(p) —NR c C(O)NR c R d ,

(q) —NR c S(O) m R e ,

(r) ═NH,

(s) —CF 3 ,

(t) —OCF 3 ,

(u) —OCHF 2 ,

(v) —C 3 -C 6 cycloalkyl,

(w) —O—C 3 -C 6 cycloalkyl,

(x) —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl,

(y) —O—C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl,

(z) HetA,

(aa) —O-HetA,

(bb) —C 1 -C 3 alkylene-HetA,

(cc) —O— C 1 -C 3 alkylene-HetA,

(dd) AryA,

(ee) —O-AryA,

(ff) —C 1 -C 3 alkylene-AryA, or

(gg) —O—C 1 -C 3 alkylene-AryA,

wherein said C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 6 cycloalkyl, —O—C 3 -C 6 cycloalkyl, —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl, —O—C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl, HetA, O-HetA, —C 1 -C 3 alkylene-HetA, —O— C 1 -C 3 alkylene-HetA, AryA, —O-AryA, —C 1 -C 3 alkylene-AryA, and —O—C 1 -C 3 alkylene-AryA are optionally substituted with one to three R a ;

L is a bond, —O—, —C 1 -C 6 alkylene-, —NHC(O)—, —C(O)—, —C(═NH)—, —S(O) m —, —SC 1 -C 6 alkylene-, —NR 3 (CH 2 ) n —, —NHC(═NH)—, or —NHS(O) m —, wherein —C 1 -C 6 alkylene-, —NHC(O)—, —C(═NH)—, —SC 1 -C 6 alkylene-, —NR 3 (CH 2 ) n —, —NHC(═NH)—, and —NHS(O) m — are optionally substituted with one to four R 7 ;

R 3 is hydrogen or —C 1 -C 3 alkyl;

M is —CH 2 OH, N(R 3 ) 2 , N + (C 1 -C 3 alkyl) 3 , C 2 -C 6 alkyl, C 3 -C 7 cycloalkyl, HetA, or AryA, wherein —CH 2 OH, N(R 3 ) 2 , N + (C 1 -C 3 alkyl) 3 , C 2 -C 6 alkyl, C 3 -C 7 cycloalkyl, HetA, and AryA are optionally substituted with one to four R 6 ;

each occurrence of R 6 is independently selected from the group consisting of: halogen, —C 1 -C 6 alkyl, —(CH 2 ) n NR c R d , —(CH 2 ) q OR e , —S(O) m R e , —S(O) m NR c R d , —C(O)R e , —OC(O)R e , —C(O)OR e , —CN, —C(O)NR c R d , —C(NH)NR c R d , —NR c R d , —N(R c )(C(O)R e ), —N(R c )(C(O)OR e ), —N(R c )(C(O)NR c R d ), —N(R c )(S(O) m R e ), HetA, and —C 1 -C 3 alkylene-HetA;

each occurrence of R 7 is independently selected from the group consisting of: halogen, —C 1 -C 6 alkyl, —(CH 2 ) n NR c R d , —(CH 2 ) q —OR e , —S(O) m R e , —S(O) m NR c R d , —C(O)R e , —OC(O)R e , —C(O)OR e , —CN, —C(O)NR c R d , —C(NH)NR c R d , —NR c R d , —N(R c )(C(O)R e ), —N(R c )(C(O)OR e ), —N(R c )(C(O)NR c R d ), —N(R c )(S(O) m R e ), HetA, and —C 1 -C 3 alkylene-HetA;

each occurrence of R c and R d is independently: hydrogen, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 3 -C 6 cycloalkyl, —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl, HetA, —C 1 -C 3 alkylene-HetA, AryA, —C 1 -C 3 alkylene-AryA, or —C 1 -C 3 alkylene-HetA, wherein each R c and R d is optionally substituted with one to three R f ;

or, alternatively, R c and R d together with the nitrogen atom to which they are attached, come together to form a 4- to 7-membered cycloheteroalkyl optionally containing one or two additional heteroatoms independently selected from O, S and —NR g ;

each occurrence of R e is independently: hydrogen, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —OH, —OC 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl, HetA, AryA, —C 1 -C 3 alkylene-AryA, or —C 1 -C 3 alkylene-HetA; wherein each R e is optionally substituted with one to three R h ;

each occurrence of R f is independently: halogen, —C 1 -C 6 alkyl, —OH, —OC 1 -C 4 alkyl, —S(O) m C 1 -C 4 alkyl, —CN, —CF 3 , —OCHF 2 , or —OCF 3 ; wherein said —C 1 -C 6 alkyl, —OC 1 -C 4 alkyl and —S(O) m C 1 -C 4 alkyl are optionally substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 ;

each occurrence of R g is independently: hydrogen, —C(O)R e , or —C 1 -C 6 alkyl, wherein said —C 1 -C 6 alkyl is optionally substituted with one to five fluorines;

each occurrence of R h is independently: halogen, —C 1 -C 6 alkyl, —OH, —OC 1 -C 4 alkyl, —S(O) m C 1 -C 4 alkyl, —CN, —CF 3 , —OCHF 2 , or —OCF 3 ; wherein said —C 1 -C 6 alkyl, —OC 1 -C 4 alkyl, and —S(O) m C 1 -C 4 alkyl are optionally substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 ;

each n is independently 0, 1, 2, 3 or 4;

each m is independently 0, 1 or 2;

each p is 1 or 2; and

each q is 0, 1, 2 or 3.

2. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

W is a bond or O;

R X and R Z are independently hydrogen, —SC 1 -C 3 alkyl, C 1 -C 3 alkyl, —(C 1 -C 3 alkylene) n OC 1 -C 3 alkyl, or —(C 1 -C 3 alkylene) n NC 1 -C 3 alkyl, wherein said —SC 1 -C 3 alkyl, C 1 -C 3 alkyl, —(C 1 -C 3 alkylene) n OC 1 -C 3 alkyl and —(C 1 -C 3 alkylene) n NC 1 -C 3 alkyl are optionally substituted with one to seven fluorines;

or, alternatively, R X and R Z , together with the carbon to which they are attached, form a monocyclic C 4 -C 7 cycloalkyl or a monocyclic C 4 -C 7 heterocycloalkyl with 1, 2, or 3 heteroatom ring atoms independently selected from N, O and S, wherein said C 4 -C 7 cycloalkyl and C 4 -C 7 heterocycloalkyl are optionally substituted with one to three substituents independently selected from —F, —OH and —OC 1 -C 3 alkyl;

X is N or CR 1 ;

R 1 is hydrogen, C 1 -C 3 alkyl, or halogen; wherein said C 1 -C 3 alkyl is optionally substituted with one to three R a ;

each occurrence of R a is independently hydrogen, halogen, C 1 -C 3 alkyl, —NR c R d or —OR e ;

Z is C 1 -C 3 alkylene, optionally substituted with one to three R b ;

each occurrence of R b is independently —C 1 -C 6 alkyl, —C 3 -C 7 cycloalkyl, —C(O)OR e , —C(O)NR c R d , tetrazolyl, oxadiazolonyl, HetA, AryA, —S(O) m R e , —S(O) m NR c R d , or P(O)(R e ) p wherein said —C 1 -C 6 alkyl and —C 3 -C 7 cycloalkyl are optionally substituted with one to three R a and wherein said AryA and HetA are optionally substituted with one to four R 4 ;

AryA is a 5- or 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S;

HetA is a 4- to 6-membered saturated or monounsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S;

Y is a bond, O, NR 2 , S, or CH 2 ;

R 2 is hydrogen, —C 1 -C 3 alkyl, —C(O)R e , —C(O)NR c R d , —S(O) m R e , or —S(O) m NR c R d , wherein said —C 1 -C 3 alkyl is optionally substituted with one to three R a ;

A 1 is a 9- to 11-membered bicyclic aromatic ring with 0, 1, 2, 3, or 4 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 ;

each occurrence of R 4 is independently:

(a) —C 1 -C 6 alkyl,

(b) —C 2 -C 6 alkenyl,

(c) —C 2 -C 6 alkynyl,

(d) halogen,

(e) —OR e ,

(f) —S(O) m R e ,

(g) —S(O) m NR c R d ,

(h) —C(O)R e ,

(i) —OC(O)R e ,

(j) —C(O)OR e ,

(k) —CN,

(l) —C(O)NR c R d ,

(m) —NR c R d ,

(n) —NR c C(O)R e ,

(o) —NR c C(O)OR e ,

(p) —NR c C(O)NR c R d ,

(q) —NR c S(O) m R e ,

(r) ═NH,

(s) —CF 3 ,

(t) —OCF 3 ,

(u) —OCHF 2 ,

(v) —C 3 -C 6 cycloalkyl,

(w) —O—C 3 -C 6 cycloalkyl,

(x) —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl,

(y) —O—C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl,

(z) HetA,

(aa) —O-HetA,

(bb) —C 1 -C 3 alkylene-HetA,

(cc) —O—C 1 -C 3 alkylene-HetA,

(dd) AryA,

(ee) —O-AryA,

(ff) —C 1 -C 3 alkylene-AryA, or

(gg) —O—C 1 -C 3 alkylene-AryA,

wherein said C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 6 cycloalkyl, —O—C 3 -C 6 cycloalkyl, —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl, —O—C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl, HetA, O-HetA, —C 1 -C 3 alkylene-HetA, —O—C 1 -C 3 alkylene-HetA, AryA, —O-AryA, —C 1 -C 3 alkylene-AryA, and −O—C 1 -C 3 alkylene-AryA are optionally substituted with one to three R a ;

L is a bond, —O—, —C 1 -C 6 alkylene-, —NHC(O)—, —C(O)—, —C(═NH)—, —S(O) m —, —SC 1 -C 6 alkylene-, —NR 3 (CH 2 ) n —, —NHC(═NH)—, or —NHS(O) m —;

R 3 is hydrogen or —C 1 -C 3 alkyl;

M is N(R 3 ) 2 , N + (C 1 -C 3 alkyl) 3 , C 2 -C 6 alkyl, C 3 -C 7 cycloalkyl, HetA, or AryA, wherein said C 2 -C 6 alkyl, C 3 -C 7 cycloalkyl, HetA, and AryA are optionally substituted with one to four R 6 ;

each occurrence of R 6 is independently selected from the group consisting of: halogen, —C 1 -C 6 alkyl, —(CH 2 ) n NR c R d , —OR e , —S(O) m R e , —S(O) m NR c R d , —C(O)R e , —OC(O)R e , —C(O)OR e , —CN, —C(O)NR c R d , —C(NH)NR c R d , —NR c R d , —N(R c )(C(O)R e ), —N(R c )(C(O)OR e ), —N(R c )(C(O)NR c R d ), and —N(R c )(S(O) m R e );

each occurrence of R c and R d is independently: hydrogen, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 3 -C 6 cycloalkyl, —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl, HetA, —C 1 -C 3 alkylene-HetA, AryA, —C 1 -C 3 alkylene-AryA, or —C 1 -C 3 alkylene-HetA, wherein each R c and R d is optionally substituted with one to three R f ;

or, alternatively, R c and R d together with the nitrogen atom to which they are attached, come together to form a 4- to 7-membered cycloheteroalkyl optionally containing one or two additional heteroatoms independently selected from O, S and —NR g ;

each occurrence of R e is independently: hydrogen, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —OH, —OC 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl, HetA, AryA, —C 1 -C 3 alkylene-AryA, or —C 1 -C 3 alkylene-HetA; wherein each R e is optionally substituted with one to three R h ;

each occurrence of R f is independently: halogen, —C 1 -C 6 alkyl, —OH, —OC 1 -C 4 alkyl, —S(O) m C 1 -C 4 alkyl, —CN, —CF 3 , —OCHF 2 , or —OCF 3 ; wherein said —C 1 -C 6 alkyl, —OC 1 -C 4 alkyl and —S(O) m C 1 -C 4 alkyl are optionally substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 ;

each occurrence of R g is independently: hydrogen, —C(O)R e , or —C 1 -C 6 alkyl, wherein said —C 1 -C 6 alkyl is optionally substituted with one to five fluorines;

each occurrence of R h is independently: halogen, —C 1 -C 6 alkyl, —OH, —OC 1 -C 4 alkyl, —S(O) m C 1 -C 4 alkyl, —CN, —CF 3 , —OCHF 2 , or —OCF 3 ; wherein said —C 1 -C 6 alkyl, —OC 1 -C 4 alkyl, and —S(O) m C 1 -C 4 alkyl are optionally substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 ;

each n is independently 0, 1, 2, 3 or 4;

each m is independently 0, 1 or 2; and

each p is 1 or 2.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CR 1 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is O.

6. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, having the Formula (IA) or (TB):

wherein:

R X and R Z are independently hydrogen, —SC 1 -C 3 alkyl, C 1 -C 3 alkyl, —(C 1 -C 3 alkylene) n OC 1 -C 3 alkyl, or —(C 1 -C 3 alkylene) n NC 1 -C 3 alkyl, wherein said —SC 1 -C 3 alkyl, C 1 -C 3 alkyl, —(C 1 -C 3 alkylene) n OC 1 -C 3 alkyl and —(C 1 -C 3 alkylene) n NC 1 -C 3 alkyl are optionally substituted with one to seven fluorines;

R b1 , R b2 , and R b3 are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —C(O)OR e , —C(O)NR c R d , tetrazolyl, oxadiazolonyl, HetA, AryA, —S(O) m R e , —S(O) m NR c R d , or —P(O)(R e ) p , wherein said C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl are optionally substituted with one to three R a and wherein said AryA and HetA are optionally substituted with one to four R 4 ;

A 1 is a 9- to 11-membered bicyclic aromatic ring containing one heteroatom ring atom selected from N and N as a quaternary salt, and containing 0, 1, 2, or 3, additional heteroatoms independently selected from N, O and S, optionally substituted with one to four R 4 ,

M is selected from the group consisting of:

(a) N(R 3 ) 2 ,

(b) N + (C 1 -C 3 alkyl) 3 ,

(c) C 3 -C 7 cycloalkyl, substituted with N(R 3 ) 2 , and optionally substituted with one to three additional substituents, independently selected from halogen, C 1 -C 3 alkyl, —NR c R d and —OR e ,

(d) a 5- or 6-membered monocyclic aromatic ring containing one heteroatom ring atom selected from N and N as a quaternary salt, and containing 0, 1, or 2 additional heteroatom ring atoms independently selected from N, O and S, optionally substituted with one to four R 6 ; and

(e) a 4- to 6-membered saturated or monounsaturated monocyclic ring containing one heteroatom ring atom selected from N and N as a quaternary salt, and containing 0, 1, or 2, additional heteroatom ring atoms independently selected from N, O and S, optionally substituted with one to four R 6 ;

and all other variables are as defined in claim 1 .

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R b1 and R b2 are independently hydrogen, C 1 -C 3 alkyl, tetrazolyl, oxadiazolonyl or —C(O)OR e ; and R b3 is hydrogen.

8. The compound of claim 1 , wherein A 1 is a 9- or 10-membered bicyclic aromatic ring containing one ring atom selected from N and N as a quaternary salt, and optionally containing an additional ring atom selected from N, O and S, optionally substituted with one or two C 1 -C 6 alkyl or halogen.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 1 is quinoline, isoquinoline, imidazo[1,2-a]pyridine, indazole, benzo[d]imidazole, benzo[d]thiazole, or naphthalene, wherein A 1 is optionally substituted with one to four R 4 .

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 1 is:

wherein ** indicates the point of attachment to L and * indicates the point of attachment to the rest of the compound.

11. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein M is: —CH 2 OH, —NH 2 , —NHCH 3 , or —N + (CH 3 ) 3 , wherein M is optionally substituted with one or two R 6 .

12. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein M is: —NH 2 , —NHCH 3 , or —N + (CH 3 ) 3 .

13. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein M is: C 3 -C 7 cycloalkyl, substituted with N(R 3 ) 2 ,

a 5- or 6-membered monocyclic aromatic ring containing one heteroatom ring atom selected from N and N as a quaternary salt, and containing 0, 1, or 2 additional heteroatom ring atoms independently selected from N, O and S, optionally substituted with one or two C 1 -C 6 alkyl; or

a 4- to 6-membered saturated or monounsaturated monocyclic ring containing one heteroatom ring atom selected from N and N as a quaternary salt, and containing 0, 1, or 2, additional heteroatom ring atoms independently selected from N, O and S, optionally substituted with one or two C 1 -C 6 alkyl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein M is:

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein M is:

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R x and R z are methyl, or R x is methyl and R z is hydrogen.

17. A compound of claim 2 , having the structure:

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1 selected from:

or a pharmaceutically acceptable salt thereof.

19. A trifluoroacetic acid salt of the compound of claim 1 .

20. A trifluoroacetic acid salt of the compounds of claim 2 .

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition according to claim 21 , which further comprises a therapeutically effective amount of one or more beta-lactamase inhibitor compounds.

23. A pharmaceutical composition according to claim 22 , wherein at least one of the one or more beta-lactamase inhibitor compounds is selected from the group consisting of relebactam, tazobactam, clavulanic acid, sulbactam, and avibactam.

24. A method for treating a bacterial infection which comprises administering to a subject in need of such treatment (i) a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, optionally in combination with one or more beta-lactamase inhibitor compounds .

25. The method of claim 24 , wherein at least one of the one or more beta-lactamase inhibitor compounds is selected from the group consisting of relebactam, tazobactam, clavulanic acid, sulbactam, and avibactam.

26. The method of claim 24 , wherein the bacterial infection is due to Pseudomonas spp., Klebsiella spp., Enterobacter spp., Escherichia spp., Morganella spp., Citrobacter spp., Serratia spp. or Acintetobacter spp.