A Phase 2, Open-Label, Multi-Center Study of Safety, Tolerability, and Efficacy of AFN-12520000 in the Treatment of Acute Bacterial Skin and Skin Structure Infections (ABSSSI) Due to Staphylococci

The purpose of the study is to determine the safety, tolerability and effectiveness of AFN-12520000 for in the treatment of Staphylococcal infections of the skin.

Start Date01 Feb 2012

Sponsor / Collaborator

Affinium Pharmaceuticals Ltd.

100 Clinical Results associated with AFN-1252

100 Translational Medicine associated with AFN-1252

100 Patents (Medical) associated with AFN-1252

Literatures (Medical) associated with AFN-1252

01 Dec 2024·Journal of Lipid Research

Prophages divert Staphylococcus aureus defenses against host lipids

Article

Author: Pagot, Charlotte ; Gaudu, Philippe ; Gruss, Alexandra ; Zhou, Biyang ; Solgadi, Audrey ; Trieu-Cuot, Patrick ; Gloux, Karine ; Pathania, Amit ; Halpern, David ; Dias-Leao, Andressa ; Pant, Deepak

Phages are ubiquitous in bacteria, including clinical Staphylococcus aureus, where Sfi 21/Sa3 phages often integrate into the hlb gene, which encodes Hlb sphingomyelinase. This integration acts as a rapid regulatory switch for Hlb production. Our findings suggest that Sfi 21/Sa3 prophages and Hlb activity influence S. aureus fitness by modulating the incorporation of the toxic linoleic acid (C18:2) from serum into the bacterial membrane. This process relies on C18:2 derived from 1,3-diglyceride, facilitated by the FakB1 kinase subunit. Palmitic acid (C16), primarily released from serum through Hlb activity, competes with C18:2 for FakB1. This mechanism contributes to adaptation to AFN-1252, an antibiotic inhibiting the fatty acid synthesis pathway (anti-FASII). Since S. aureus relies on exogenous fatty acids for growth, AFN-1252 treatment leads to an increased proportion of C18:2 in the membrane. Furthermore, Hlb inhibition, whether by prophage insertion, gene inactivation, or enzyme inhibition, delays S. aureus adaptation, resulting in a higher proportion of C18:2 in the membrane. This study sheds light on the role of lipid environments in infections and may contribute to the accurate prediction of infection risks and therapeutic efficacy. Moreover, since both anti-FASII agent and Hlb inhibitor enhance C18:2 incorporation, they represent potential candidates for combined strategies against S. aureus.

27 Jun 2024·Journal of Medicinal Chemistry

Discovery and Optimization of Novel SaFabI Inhibitors as Specific Therapeutic Agents for MRSA Infection

Article

Author: Ju, Yuan ; Chen, Baoyi ; Zhang, Laiying ; Luo, Baozhu ; Gou, Xupeng ; Zhang, Jiangnan ; He, Lei ; Liu, Yan ; Wang, Yanmei ; Yang, Tao ; Sui, Jing ; Yang, Jiaxing ; Tao, Tao ; Luo, Youfu ; Qiu, Zhiqiang ; Xu, Xin

As the rate-limiting enzyme in fatty acid biosynthesis, Staphylococcus aureus enoyl-acyl carrier protein reductase (SaFabI) emerges as a compelling target for combating methicillin-resistant S. aureus (MRSA) infections. Herein, compound 1, featuring a 4-(1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one scaffold, was identified as a potent SaFabI inhibitor (IC₅₀ = 976.8 nM) from an in-house library. Subsequent optimization yielded compound n31, with improved inhibitory efficacy on enzymatic activity (IC₅₀ = 174.2 nM) and selective potency against S. aureus (MIC = 1-2 μg/mL). Mechanistically, n31 directly inhibited SaFabI in cellular contexts. Moreover, n31 exhibited favorable safety and pharmacokinetic profiles, and dose-dependently treated MRSA-induced skin infections, outperforming the approved drug, linezolid. The chiral separation of n31 resulted in (S)-n31, with superior activities (IC₅₀ = 94.0 nM, MIC = 0.25-1 μg/mL) and in vivo therapeutic efficacy. In brief, our research proposes (S)-n31 as a promising candidate for SaFabI-targeted therapy, offering specific anti-S. aureus efficacy and potential for further development.

01 Apr 2024·iScience

Oxidative stress is intrinsic to staphylococcal adaptation to fatty acid synthesis antibiotics

Article

Author: Page, Adeline ; Kénanian, Gérald ; Anba-Mondoloni, Jamila ; Halpern, David ; Lavergne, Jean-Pierre ; Millan-Oropeza, Aaron ; Wongdontree, Paprapach ; Grangeasse, Christophe ; Henry, Céline ; Gloux, Karine ; Gruss, Alexandra ; Fouet, Agnès ; Upfold, Jennifer ; Lambert, Clara

Antibiotics inhibiting the fatty acid synthesis pathway (FASII) of the major pathogen Staphylococcus aureus reach their enzyme targets, but bacteria continue growth by using environmental fatty acids (eFAs) to produce phospholipids. We assessed the consequences and effectors of FASII-antibiotic (anti-FASII) adaptation. Anti-FASII induced lasting expression changes without genomic rearrangements. Several identified regulators affected the timing of adaptation outgrowth. Adaptation resulted in decreased expression of major virulence factors. Conversely, stress responses were globally increased and adapted bacteria were more resistant to peroxide killing. Importantly, pre-exposure to peroxide led to faster anti-FASII-adaptation by stimulating eFA incorporation. This adaptation differs from reports of peroxide-stimulated antibiotic efflux, which leads to tolerance. In vivo, anti-FASII-adapted S. aureus killed the insect host more slowly but continued multiplying. We conclude that staphylococcal adaptation to FASII antibiotics involves reprogramming, which decreases virulence and increases stress resistance. Peroxide, produced by the host to combat infection, favors anti-FASII adaptation.

100 Deals associated with AFN-1252

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Indication	Highest Phase	Country/Location	Organization	Date
Skin and skin structure infections	Phase 2	-	GSK Plc	-
Burn infections	Phase 1	United States	Affinium Pharmaceuticals Ltd.	01 Feb 2012
Burn infections	Phase 1	Canada	Affinium Pharmaceuticals Ltd.	01 Feb 2012
Cellulitis	Phase 1	United States	Affinium Pharmaceuticals Ltd.	01 Feb 2012
Cellulitis	Phase 1	Canada	Affinium Pharmaceuticals Ltd.	01 Feb 2012
Skin Diseases, Bacterial	Phase 1	Canada	Affinium Pharmaceuticals Ltd.	01 Feb 2012
Skin Diseases, Bacterial	Phase 1	United States	Affinium Pharmaceuticals Ltd.	01 Feb 2012
Wound Infection	Phase 1	United States	Affinium Pharmaceuticals Ltd.	01 Feb 2012
Wound Infection	Phase 1	Canada	Affinium Pharmaceuticals Ltd.	01 Feb 2012
Complicated skin and soft tissue infection	Phase 1	United States	Debiopharm International SA	31 Jan 2012

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01519492 (Pubmed \| Antimicrob Agents Chemother) Manual	Phase 2	Skin and skin structure infections	103	AFN-1252	(fcrezhntln) = headache (26.2%) and nausea (21.4%) bwjarkvvkw (evzwtgfcju )	Positive	28 Dec 2015

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