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 Nov 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 ; Halpern, David ; Gloux, Karine ; Pathania, Amit ; 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 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.

20 Dec 2023·mSphere

Elucidating the impact of bacterial lipases, human serum albumin, and FASII inhibition on the utilization of exogenous fatty acids by Staphylococcus aureus

Article

Author: Pruitt, Emily L ; Chen, Xi ; Werth, Brian J ; Bush, Matthew F ; Ashford, Nathaniel K ; Ross, Dylan H ; Zhang, Rutan ; Alonzo, Francis ; Xu, Libin

ABSTRACTStaphylococcus aureus only synthesizes straight-chain saturated fatty acids (SCFAs) or branched-chain saturated fatty acids via the type II fatty acid synthesis (FASII) pathway, but as a highly adaptive pathogen, S. aureus can also utilize host-derived exogenous fatty acids (eFAs), including SCFAs and unsaturated fatty acids (UFAs). S. aureus secretes three lipases, glycerol ester hydrolase (Geh), S. aureus lipase 1, and SAUSA300_0641, which could release fatty acids from host lipids. Once released, the FAs are phosphorylated by the fatty acid kinase and incorporated into the bacterial lipids. In this study, we determined the substrate specificity of S. aureus secreted lipases, the effect of human serum albumin (HSA) on eFA incorporation, and the effect of FASII inhibitor AFN-1252 on eFA incorporation using comprehensive lipidomics. When grown with major donors of fatty acids, cholesteryl esters (CEs) and triglycerides (TGs), Geh was found to be the primary lipase responsible for hydrolyzing CEs, but other lipases could compensate for the function of Geh in hydrolyzing TGs. Lipidomics showed that eFAs were incorporated into all major S. aureus lipid classes and that fatty acid-containing HSA can serve as a source of eFAs. Furthermore, S. aureus grown with UFAs displayed increased membrane fluidity and increased production of reactive oxygen species (ROS). Exposure to AFN-1252 enhanced UFAs in the bacterial membrane, even without a source of eFAs, indicating the inhibition of double bond reduction by FabI. Thus, the incorporation of eFAs alters the S. aureus lipidome, membrane fluidity, and ROS formation, which could affect host-pathogen interactions and susceptibility to membrane-targeting antimicrobials. IMPORTANCE Incorporation of host-derived exogenous fatty acids (eFAs), particularly unsaturated fatty acids (UFAs), by Staphylococcus aureus could affect the bacterial membrane fluidity and susceptibility to antimicrobials. In this work, we found that glycerol ester hydrolase (Geh) is the primary lipase hydrolyzing cholesteryl esters and, to a lesser extent, triglycerides and that human serum albumin (HSA) could serve as a buffer of eFAs, where low levels of HSA facilitate the utilization of eFAs but high levels of HSA inhibit it. The fact that the type II fatty acid synthesis (FASII) inhibitor, AFN-1252, leads to an increase in UFA content even in the absence of eFA suggests that membrane property modulation is part of its mechanism of action. Thus, Geh and/or the FASII system look to be promising targets to enhance S. aureus killing in a host environment by restricting eFA utilization or modulating membrane properties, respectively.

30 Jun 2023·bioRxiv : the preprint server for biology

Elucidating the Impact of Bacterial Lipases, Human Serum Albumin, and FASII Inhibition on the Utilization of Exogenous Fatty Acids by Staphylococcus aureus.

Author: Pruitt, Emily L ; Chen, Xi ; Werth, Brian J ; Bush, Matthew F ; Ashford, Nathaniel K ; Ross, Dylan H ; Zhang, Rutan ; Alonzo, Francis ; Xu, Libin

Staphylococcus aureus only synthesizes straight-chain or branched-chain saturated fatty acids (SCFAs or BCFAs) via the type II fatty acid synthesis (FASII) pathway, but as a highly adaptive pathogen, S. aureus can also utilize host-derived exogenous fatty acids (eFAs), including SCFAs and unsaturated fatty acids (UFAs). S. aureus secretes three lipases, Geh, sal1, and SAUSA300_0641, which could perform the function of releasing fatty acids from host lipids. Once released, the FAs are phosphorylated by the fatty acid kinase, FakA, and incorporated into the bacterial lipids. In this study, we determined the substrate specificity of S. aureus secreted lipases, the effect of human serum albumin (HSA) on eFA incorporation, and the effect of FASII inhibitor, AFN-1252, on eFA incorporation using comprehensive lipidomics. When grown with major donors of fatty acids, cholesteryl esters (CEs) and triglycerides (TGs), Geh was found to be the primary lipase responsible for hydrolyzing CEs, but other lipases could compensate for the function of Geh in hydrolyzing TGs. Lipidomics showed that eFAs were incorporated into all major S. aureus lipid classes and that fatty acid-containing HSA can serve as a source of eFAs. Furthermore, S. aureus grown with UFAs displayed decreased membrane fluidity and increased production of reactive oxygen species (ROS). Exposure to AFN-1252 enhanced UFAs in the bacterial membrane, even without a source of eFAs, indicating a FASII pathway modification. Thus, the incorporation of eFAs alters the S. aureus lipidome, membrane fluidity, and ROS formation, which could affect host-pathogen interactions and susceptibility to membrane-targeting antimicrobials.

100 Deals associated with AFN-1252

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12658

R&D Status

10 top R&D records.

to view more data

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

Clinical Result

Indication

Phase

Evaluation

View All Results

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	(uozwbkklbk) = headache (26.2%) and nausea (21.4%) fbtjzmryhc (vabwvdefxl )	Positive	28 Dec 2015

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

AFN-1252

Overview

Basic Info

Structure

Related

External Link

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation