P104 A Novel Synthetic Boronic Acid Ester With A Broad Spectrum of Antibacterial Activity

Weimin Mao1, L. Kohut2, J. Khan2 and M.R.K. Alley1

1Anacor Pharmaceuticals Inc., 1060 East Meadow Circle, Palo Alto, CA 94303, USA; 2NAEJA Pharmaceutical Inc., #2, 4290 91A Street, Edmonton, AB, T6E 5V2, Canada

FIGURE 1. Structure of AN0128 (3- Me

ABSTRACT TABLE 2. MIC90 (μg/mL) values of AN0128 compared with clindamycin
hydroxypyridine-2-carbonyloxy- Cl
AN0128 is a novel borinic acid ester with combined antimicrobial and anti- against sensitive and resistant P. acnes and P. granulosum.
inflammatory activity. This poster reports the following results:
bis(3-chloro-4-methylphenyl)-
borane) O O AN0128
¾AN0128 has broad-spectrum antibacterial activity against low GC Gram- MIC MIC50 MIC90
positive bacteria with MIC values ranging from 0.125-2 μg/mL. Cl B Organism Total Range
OH
¾ AN0128 has good activity against Gram-negative bacteria of the N P. acnes 33 2.0 2.0 2.0
Bacteroides class with MIC values of 0.125-2 μg/mL. P. acnes ErmR or TetR or ClnR 2.0 - 4.0 2.0 2.0
Me 59
¾AN0128 has an MIC90 value of 4 μg/mL against Propionibacterium acnes P. granulosum 4 2.0 - 4.0 2.0 4.0
and P. granulosum regardless of clindamycin, erythromycin or tetracycline TABLE 1. MIC (μg/mL) values of AN0128 against wide panel of P. granulosum ErmR 14 2.0 - 4.0 2.0 4.0
susceptibility.
both Gram-negative and Gram-positive bacteria. Ciindamycin
¾ AN0128 has an MIC90 value of 4 μg/ml against S. epidermidis regardless of
clindamycin or erythromycin susceptibility. MIC MIC50 MIC90
Organism Total
¾AN0128 has an MIC90 value of 1 μg/mL against MSSA and MRSA Range

AN0128
P. acnes 33 0.06-0.125 0.06 0.125
Staphylococcus aureus.
P. acnes ErmR or TetR or ClnR 59 0.125-512 16 512
Bacteria P. granulosum 4 0.0625-0.5 0.0625 0.5
INTRODUCTION P. granulosum ErmR 2.0-512 256 512
Bacillus cereus ATCC 1178 0.5 14
The continual battle to maintain the efficacy of antibiotics in the face of the rapid rise ErmR = erythromycin resistant, TetR = tetracycline resistant, ClnR = clindamycin
of bacterial resistance necessitates the need to develop novel classes of antibacterial Clostridium difficile ATCC 9689 1 resistant
compounds. In this study we have tested AN0128 (3-hydroxypyridine -2- Enterococcus faecalis ATCC 19433 2
carbonyloxy-bis(3-chloro-4-methylphenyl)-borane against a broad panel of Gram-
positive and Gram-negative bacteria. Enterococcus faecalis ATCC 700802 VanR 2 TABLE 3. MIC90 (μg/mL) values of AN0128 compared with clindamycin
Gram-positive Enterococcus faecium CT-26 2 against sensitive and resistant S. epidermidis.

Low GC
METHODS Enterococcus faecium ATCC 700221 VanR 2
Minimal inhibitory concentrations (MIC) were determined as outlined by the CLSI
AN0128
Eubacterium nodatum ATCC 33099 0.25 MIC MIC50 MIC90
(formerly NCCLS) guidelines with exception that streptococcal MICs were Organism Total Range
performed in the absence of lysed horse blood. MICs against Propionibacterium spp Staphylococcus aureus ATCC 29213 1 S. epidermidis 30 1.0-4.0 2.0 4.0
were obtained in the absence of laked sheep blood. Staphylococcus epidermidis ATCC 12228 2 S. epidermidis ErmR and ClnR 30 1.0-16 2.0 4.0
Streptococcus mutans ATCC 25175 1 Ciindamycin
RESULTS and DISCUSSION
MIC MIC50 MIC90
AN0128 is a member of a new class of antibiotics that has activity against Gram- Streptococcus pneumoniae ATCC 6301 ≤ 0.12 Organism Total Range
positive and anaerobic Gram-negatives from the Bacteroides class (Table 1). The Streptococcus pyogenes ATCC 19615 0.25 S. epidermidis 30 0.06-0.125 0.125 0.125
activity is not affected by vancomycin resistance in enterococci (Table 1) or
S. epidermidis ErmR and ClnR 30 >32 >32 >32
macrolide and tetracycline resistance in Propionibacterium spp (Table 2). The Mycobacterium tuberculosis ATCC 25177 16
High GC

ErmR = erythromycin resistant, ClnR = clindamycin resistant

presence of macrolide or methicillin resistance in staphylococci also does not affect Mycobacterium avium ATCC 25291 > 32
the MIC90 values for AN0128 (Table 3 and 4). Furthermore the spontaneous
frequency of resistance to AN0128 is extremely low, less than < 1.3 x 10-11 for S. Propionibacterium acnes ATCC 6919 2
aureus and < 8.8 x 10-11 for P. acnes. Propionibacterium granulosum NCTC 11865 2 TABLE 4. MIC90 (μg/mL) values of AN0128 compared with ciprofloxacin
against S. aureus MSSA and MRSA strains.
Bacteroides

Bacteroides fragilis ATCC 25285 2

CONCLUSIONS
Gram-negative

Porphyromonas gingivalis ATCC 33277 ≤ 0.12 AN0128

AN0128, a novel compound in development for the topical treatment of
Prevotella intermedia ATCC 25611 MIC Range MIC50 MIC90
acne vulgaris and atopic dermatitis exhibits: 0.25 Organism Total
¾Broad-spectrum antibacterial activity with MIC90 values against Tannerella forsythensis ATCC 43037 ≤ 0.12 S. aureus MSSA 17 1.0 1.0 1.0
Staphylococcus spp and Propionibacterium spp ranging from 1-4 S. aureus MRSA 15 0.5-1.0 1.0 1.0
Escherichia coli ATCC 25922 >64
μg/mL. Ciprofloxacin
Haemophilus influenzae ATCC 49766 >64 MIC Range MIC50 MIC90
¾MIC90 values for AN0128 are not affected by Staphylococcus spp Organism Total
and Propionibacterium spp resistance to macrolides, tetracycline,
Helicobacter pylori 26695 8
S. aureus MSSA 17 <0.125-0.25 0.25 0.25
ciprofloxacin or methicillin. Pseudomonas aeruginosa ATCC 27853 >64 S. aureus MRSA 15 <0.125->64 >64 >64
Treponema denticola ATCC 35405 8
VanR = vancomycin resistant
Poster will be available at www.anacor.com after March 7, 2006