The ABC-Type Efflux Pump MacAB Is Involved in Protection of Serratia marcescens against Aminoglycoside Antibiotics, Polymyxins, and Oxidative Stress

Abstract

Serratia marcescens is an emerging pathogen with increasing clinical importance due to its intrinsic resistance to several classes of antibiotics. The chromosomally encoded drug efflux pumps contribute to antibiotic resistance and represent a major challenge for the treatment of bacterial infections. The ABC-type efflux pump MacAB was previously linked to macrolide resistance in Escherichia coli and Salmonella enterica serovar Typhimurium. The role of the MacAB homolog in antibiotic resistance of S. marcescens is currently unknown. We found that an S. marcescens mutant lacking the MacAB pump did not show increased sensitivity to the macrolide antibiotic erythromycin but was significantly more sensitive to aminoglycoside antibiotics and polymyxins. We also showed that, in addition to its role in drug efflux, the MacAB efflux pump is required for swimming motility and biofilm formation. We propose that the motility defect of the ΔmacAB mutant is due, at least in part, to the loss of functional flagella on the bacterial surface. Furthermore, we found that the promoter of the MacAB efflux pump was active during the initial hours of growth in laboratory medium and that its activity was further elevated in the presence of hydrogen peroxide. Finally, we demonstrate a complete loss of ΔmacAB mutant viability in the presence of peroxide, which is fully restored by complementation. Thus, the S. marcescens MacAB efflux pump is essential for survival during oxidative stress and is involved in protection from polymyxins and aminoglycoside antibiotics. IMPORTANCE The opportunistic pathogen Serratia marcescens can cause urinary tract infections, respiratory infections, meningitis, and sepsis in immunocompromised individuals. These infections are challenging to treat due to the intrinsic resistance of S. marcescens to an extensive array of antibiotics. Efflux pumps play a crucial role in protection of bacteria from antimicrobials. The MacAB efflux pump, previously linked to efflux of macrolides in Escherichia coli and protection from oxidative stress in Salmonella enterica serovar Typhimurium, is not characterized in S. marcescens. We show the role of the MacAB efflux pump in S. marcescens protection from aminoglycoside antibiotics and polymyxins, modulation of bacterial motility, and biofilm formation, and we illustrate the essential role for this pump in bacterial survival during oxidative stress. Our findings make the MacAB efflux pump an attractive target for inhibition to gain control over S. marcescens infections.

Antimicrobial Activities of Secondary Metabolites from Model Mosses

“…Broth microdilution method to determine minimum inhibitory concentration (MIC). A determination of minimum inhibitory concentration (MIC) of moss metabolites was performed using 96-well microtiter plates in a BioTek plate reader spectrophotometer, the Synergy HTX [ 36 ]. Bacterial cultures were grown ON at 35 °C in MH (Mueller–Hinton) broth.…”

Occurrence of Serratia marcescens Carrying blaIMP-26 and mcr-9 in Southern China: New Insights in the Evolution of Megaplasmid IMP-26

“…S. marcescens is an opportunistic nosocomial pathogen and is intrinsically multidrug resistant, mainly due to the presence of a large number of efflux pump genes [ 48 , 49 ], with the ability to produce myriad extracellular enzymes as well as metabolites which make it capable of adapting to both hostile and changing environments [ 50 , 51 , 52 ]. In S. marcescens , the PhoPQ system can regulate the expression of the arn operon by sensing polymyxin B (PB) and Mg 2+ , which results in the LPS being modified and leads to PB resistance [ 53 , 54 ].…”

Formic acid, an organic acid food preservative, induces viable-but-non-culturable state, and triggers new Antimicrobial Resistance traits in Acinetobacter baumannii and Klebsiella pneumoniae

“…Both OmpH and OmpA are molecular markers for virulence also ( Confer and Ayalew, 2013 ; Khamesipour et al, 2014 ). ABC transporter MacAB is involved in bacterial resistance against multiple antibiotics, antimicrobial peptides, and non-antibiotic xenobiotics and chemicals (arsenite) ( Shi et al, 2019 ; Shirshikova et al, 2021 ). ABC transporter genes were also shown to be upregulated in VBNC induction ( Liu et al, 2016 ).…”