Study on collateral sensitivity of tigecycline to colistin-resistant Enterobacter cloacae complex

Area of Science:

• Microbiology
• Molecular Biology
• Pharmacology

Background:

• Carbapenem-resistant Enterobacter cloacae complex (CRECC) poses a significant global health threat due to escalating antimicrobial resistance (AMR).
• Novel strategies are crucial to combat the spread of multidrug-resistant bacteria and overcome treatment limitations.

Purpose of the Study:

• To investigate the phenomenon of collateral sensitivity in CRECC following tigecycline (TGC) exposure.
• To evaluate the impact of TGC on colistin (COL) susceptibility in CRECC isolates.
• To explore the potential of combination therapy using TGC and COL against CRECC.

Main Methods:

• Induction of tigecycline resistance in clinical CRECC isolates.
• Assessment of colistin susceptibility in tigecycline-resistant mutants.
• Gene expression analysis (acrA, acrB, ramA, ramR, phoQ, arnA) and mutation screening (lipid A synthesis genes).
• Evaluation of antimicrobial efficacy of monotherapy versus combination therapy (low-dose COL + TGC).

Main Results:

• Tigecycline pressure converted colistin resistance to sensitivity in five clinical CRECC strains.
• Tigecycline-resistant mutants showed increased expression of acrA, acrB, and ramA genes, linked to ramR mutations.
• Downregulation of phoQ and variable arnA expression were observed, impacting lipid A modification.
• Combination therapy with low-dose colistin and tigecycline demonstrated superior antimicrobial efficacy compared to monotherapy.

Conclusions:

• Collateral sensitivity to tigecycline can re-sensitize colistin-resistant CRECC to colistin.
• The overexpression of efflux pump genes (acrA, acrB, ramA) due to ramR mutations drives tigecycline resistance.
• Downregulation of phoQ and arnA contributes to increased colistin sensitivity.
• Synergistic tigecycline and colistin combination therapy offers a promising strategy to combat CRECC infections and mitigate AMR.