Determining Susceptibility and Potential Mediators of Resistance for the Novel Polymyxin Derivative, SPR206, in
Jacinda C Abdul-Mutakabbir1,2,3, Nana Sakyi Opoku3, Karen K Tan4
1Division of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA.
Abstract:
With the increase in carbapenem-resistant A. baumannii (CRAB) infections, there has been a resurgence in the use of polymyxins, specifically colistin (COL). Since the reintroduction of COL-based regimens in treating CRAB infections, several COL-resistant A. baumannii isolates have been identified, with the mechanism of resistance heavily linked with the loss of the lipopolysaccharide (LPS) layer of the bacterial outer membrane through mutations in lpxACD genes or the pmrCAB operon. SPR206, a novel polymyxin derivative, has exhibited robust activity against multidrug-resistant (MDR) A. baumannii. However, there is a dearth of knowledge regarding its efficacy in comparison with other A. baumannii-active therapeutics and whether traditional polymyxin (COL) mediators of A. baumannii resistance also translate to reduced SPR206 activity. Here, we conducted susceptibility testing using broth microdilution on 30 A. baumannii isolates (17 COL-resistant and 27 CRAB), selected 14 COL-resistant isolates for genomic sequencing analysis, and performed time-kill analyses on four COL-resistant isolates. In susceptibility testing, SPR206 demonstrated a lower range of minimum inhibitory concentrations (MICs) compared with COL, with a four-fold difference observed in MIC50 values. Mutations in lpxACD and/or pmrA and pmrB genes were detected in each of the 14 COL-resistant isolates; however, SPR206 maintained MICs ≤ 2 mg/L for 9/14 (64%) of the isolates. Finally, SPR206-based combination regimens exhibited increased synergistic and bactericidal activity compared with COL-based combination regimens irrespective of the multiple resistance genes detected. The results of this study highlight the potential utility of SPR206 in the treatment of COL-resistant A. baumannii infections.
Insights
A new polymyxin derivative, SPR206, shows promise against colistin-resistant Acinetobacter baumannii infections. SPR206 maintained activity even with resistance mechanisms and demonstrated superior synergistic and bactericidal effects in combination therapies.
Area of Science:
- Microbiology and Infectious Diseases
- Antimicrobial Resistance
- Pharmacology
Background:
- Rising carbapenem-resistant Acinetobacter baumannii (CRAB) infections have increased reliance on colistin (COL).
- Emergence of COL-resistant A. baumannii strains, often due to LPS modification via lpxACD or pmrCAB mutations, poses a significant clinical challenge.
- Limited understanding exists regarding the efficacy of novel polymyxin derivatives like SPR206 against CRAB and whether established COL resistance mechanisms affect SPR206 activity.
Purpose of the Study:
- To evaluate the in vitro activity of SPR206 against colistin-resistant (COL-R) and carbapenem-resistant (CRAB) Acinetobacter baumannii isolates.
- To compare SPR206 efficacy with colistin (COL) in susceptibility and time-kill assays.
- To investigate if known COL resistance mechanisms impact SPR206 susceptibility and to assess SPR206 in combination therapies.
Main Methods:
- Broth microdilution susceptibility testing was performed on 30 A. baumannii isolates (17 COL-R, 27 CRAB).
- Genomic sequencing was conducted on 14 COL-R isolates to identify resistance genes (lpxACD, pmrCAB).
- Time-kill analyses were performed on four COL-R isolates using SPR206 and COL, alone and in combination regimens.
Main Results:
- SPR206 exhibited lower minimum inhibitory concentrations (MICs) than COL, with a four-fold lower MIC50.
- Despite the presence of lpxACD and/or pmrA/B mutations in all 14 sequenced COL-R isolates, SPR206 remained active (MIC ≤ 2 mg/L) in 64% (9/14) of them.
- SPR206-based combination regimens demonstrated enhanced synergistic and bactericidal activity compared to COL-based regimens, regardless of detected resistance genes.
Conclusions:
- SPR206 demonstrates potent in vitro activity against a significant proportion of colistin-resistant Acinetobacter baumannii isolates.
- The compound retains efficacy even in isolates possessing common colistin resistance mechanisms.
- SPR206 shows considerable potential as a therapeutic option for treating challenging colistin-resistant A. baumannii infections, particularly in combination therapies.
