Post on 08-Aug-2020
Potent Activity of a Novel Gyrase Inhibitor (SPR719/SPR720) In Vitro and in a Prolonged Acute Mycobacterium abscessus Mouse Model of Infection
A Rubio1, M Stapleton2, D Verma2, D Ordway2
1Spero Therapeutics, Cambridge, MA; 2Colorado State University, Fort Collins, CO
A Rubio
June 10, 2018
SUN-539
Background: Mycobacterium abscessus, a fast-growing mycobacterial species, has
emerged in recent years as an important opportunistic pathogen increasingly
responsible for mortality with extremely limited therapeutic options available. Here we
evaluate the in vitro and in vivo activity of SPR719 and it’s phosphate prodrug,
SPR720, against M. abscessus 103 in a prolonged acute SCID mouse model of M. abscessus infection.
Methods: MIC testing was performed by microbroth dilution method using cation
adjusted Mueller Hinton broth, consistent with M7-A7 CLSI methodology against
clinical strains of M. abscessus. To assess efficacy, SCID female mice received an
intravenous infection with 1x106 CFU/mouse of M. abcessus subsp boletti strain 103.
Three mice were sacrificed after day one of infection (PI) to determine bacterial uptake
(lungs, spleens and livers). SPR720 was administered orally (PO) (400, 300, 200, 100,
50 and 25 mg/kg q24h) starting 2 days PI and continued for 16 days. Clarithromycin
(CLR) was administered PO at 250 mg/kg q24h. Mice were sacrificed 24 h after the
last dose with whole organ bacterial loads evaluated.
Results: SPR719 had potent activity against M. abscessus 103, M. abscessus 21
and M. abscessus 1513 strains (MIC in mg/L of 1, 1 and 2, respectively) compared to
CLR (MIC >4 mg/L) and amikacin (>8 mg/L). In the efficacy study, no significant weight
loss or clinical observations in the lungs, spleens or livers were noted for any of the
SPR720 treated groups. Resulting burdens are shown in the table. CLR served as a
positive control and behaved as expected. SPR720 at 100 mg/kg q24h demonstrated
the greatest reduction in bacterial burden in the lung (p<0.0001), spleen (p<0.0001),
and liver (p<0.0001) compared to the M. abscessus day 17 infected control.
Conclusions: SPR719 displayed potent activity in all of the clinical strains tested in vitro. SPR720 siginificantly reduced the bacterial burden in lungs, spleens and livers
in a prolonged SCID treatment mouse model. These findings support the further
advancement of SPR720 for the treatment of nontuberculosis mycobacterial disease.
• MIC testing of SPR719 was performed by microbroth dilution using
cation ion adjusted Mueller Hinton broth, consistent with M24-A2 CLSI
methodology1
• To assess efficacy, SCID mice were infected using M. abscessussubsp bolletti 103 via tail vein injection as described previously2
• SPR720 or clarithromycin treatment initiated on day 2 and continued
for 16 days with mice sacrificed 24 h after the last dose
ABSTRACT
CONCLUSIONS
INTRODUCTION
Aileen Rubio
Spero Therapeutics
675 Massachusetts Ave
Cambridge, MA 02139
arubio@sperotx.com
N
NH
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HNHN
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N
N O P OHO
OHN
NH
O
HNHN
OF
N
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Figure 2. Structures of SPR719 (active) and SPR720 (prodrug)
Table 1. MIC (mg/L) values against M. abscessus strains
CompoundM. abscessus Strain Number
103 21 1513SPR719 1 1 2
Clarithromycin (CLR) >4 >4 >4
Amikacin (AMK) >8 >8 >8
• SPR719 was more potent than CLR or AMK against M. abscessus 103
• No significant weight loss or clinical observations in the lungs, spleen or
livers were noted for any of the SPR720 treated groups
• CLR served as a positive control in the acute infection model and
behaved as expected
• SPR720 at 100 mg/kg q24h demonstrated the greatest reduction in
bacterial burden in the lung, spleen and liver (p<0.0001) compared to the
day 17 control
REFERENCES
• The novel gyrase inhibitor displayed potent activity in vitro against
strains of M. abscessus• SPR720 treatment significantly reduced the bacterial burden in the
lungs, spleens and livers of SCID mice infected with strains of M.abscessus• These findings support the further development of SPR720 for the
treatment of NTM infections
1. CLSI (2011) M24-A2
2. Obregon A., Arnett K., Henao M., Massoudi L., Creissen E.,
Andries K., Lenaerts A.J., Ordway D.J. 2015. Susceptibility of
Mycobacterium abscessus to anti-mycobacterial drugs in
preclinical models. AAC. 59:6904-12
Figure 1. Burden in lung, spleen and liver after 16 days of treatment in a prolonged acute SCID mouse infection caused by M. abscessus 103
• Infections caused by nontuberculosis mycobacteria (NTM) are
increasing in prevalence due to improved recognition and diagnosis.
• NTM infections are generally difficult to treat since these organisms
are resistant to most of the antituberculosis drugs and therefore new
agents are needed
• M. avium complex (MAC) and M. abscessus are the most common
pathogens found
• M. abscessus is a rapid growing mycobacterium (RGM) that has
recently emerged as an important opportunistic pathogen
• Here we evaluate the in vitro and in vivo activity of SPR719 and it’s
phosphate prodrug, SPR720, against M. abscessus 103 in a
prolonged acute SCID mouse model of M. abscessus infection
RESULTS
Treatment Group NBurden (Log10 CFU)
Lung Spleen Liver
Day 2 3 4.1 5.1 6.1
Day 17 5 5.7 5.6 6.2
CLR 5 3.9 3.8 5.6
SPR720 – 400 5 3.1 3.7 5.3
SPR720 – 300 5 3.4 3.7 5.6
SPR720 – 200 5 3.4 3.1 4.9
SPR720 – 100 5 2.6 2.9 4.0
SPR720 – 50 5 3.6 3.6 5.6
SPR720 – 25 5 3.9 3.6 5.3
day 1 day 17 720 - 25 720 - 50 720 - 100 720 - 200 720 - 300 720 - 400 CLR - 2500
2
4
6
log
CF
U/g
Lu
ng
Tis
su
e
day 1 day 17 720 - 25 720 - 50 720 - 100 720 - 200 720 - 300 720 - 400 CLR - 2500
2
4
6
log
CF
U/g
Sp
leen
Tis
su
e
day 1 day 17 720 - 25 720 - 50 720 - 100 720 - 200 720 - 300 720 - 400 CLR - 2500
2
4
6
log
CF
U/g
Liv
er
Tis
su
e
Lung burden Spleen burden Liver burden
Table 2. Burden in lung, spleen and liver after 16 days
of treatment
METHODS