The Antibiotic Efflux Protein TolC Is a Highly Evolvable Target under Colicin E1 or TLS Phage Selection

被引:17
|
作者
Tamer, Yusuf Talha [1 ]
Gaszek, Ilona [1 ]
Rodrigues, Marinelle [1 ]
Coskun, Fatma Sevde [2 ]
Farid, Michael [3 ]
Koh, Andrew Y. [4 ,5 ]
Russ, William [1 ,6 ]
Toprak, Erdal [1 ,7 ]
机构
[1] Univ Texas Southwestern Med Ctr Dallas, Green Ctr Syst Biol, Dallas, TX 75390 USA
[2] Univ Texas Southwestern Med Ctr Dallas, Dept Immunol, Dallas, TX 75390 USA
[3] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA
[4] Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Dallas, TX USA
[5] Univ Texas Southwestern Med Ctr Dallas, Dept Microbiol, Dallas, TX USA
[6] Univ Texas Southwestern Med Ctr Dallas, Ctr Alzheimers & Neurodegenerat Dis, Dallas, TX 75390 USA
[7] Univ Texas Southwestern Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA
关键词
systems biology; protein evolution; deep mutational scanning; bacterial evolution; bacteriophages; antibiotic resistance; BACTERIAL EXIT DUCT; OUTER-MEMBRANE; MULTIDRUG EFFLUX; EXPORT; EXPRESSION; RESISTANCE; MUTANTS; THERAPY; FITNESS; IMPORT;
D O I
10.1093/molbev/msab190
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Bacteriophages and bacterial toxins are promising antibacterial agents to treat infections caused by multidrug-resistant (MDR) bacteria. In fact, bacteriophages have recently been successfully used to treat life-threatening infections caused by MDR bacteria (Schooley RT, Biswas B, Gill JJ, Hernandez-Morales A, Lancaster J, Lessor L, Barr JJ, Reed SL, Rohwer F, Benler S, et al. 2017. Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection. Antimicrob Agents Chemother. 61(10); Chan BK, Turner PE, Kim S, Mojibian HR, Elefteriades JA, Narayan D. 2018. Phage treatment of an aortic graft infected with Pseudomonas aeruginosa. Evol Med Public Health. 2018(1):60-66; Petrovic Fabijan A, Lin RCY, Ho J, Maddocks S, Ben Zakour NL, Iredell JR, Westmead Bacteriophage Therapy Team. 2020. Safety of bacteriophage therapy in severe Staphylococcus aureus infection. Nat Microbiol. 5(3):465-472). One potential problem with using these antibacterial agents is the evolution of resistance against them in the long term. Here, we studied the fitness landscape of the Escherichia coli TolC protein, an outer membrane efflux protein that is exploited by a pore forming toxin called colicin E1 and by TLS phage (Pagie L, Hogeweg P. 1999. Colicin diversity: a result of eco-evolutionary dynamics. J Theor Biol. 196(2):251-261; Andersen C, Hughes C, Koronakis V. 2000. Chunnel vision. Export and efflux through bacterial channel-tunnels. EMBO Rep. 1(4):313-318; Koronakis V, Andersen C, Hughes C. 2001. Channel-tunnels. Curr Opin Struct Biol. 11(4):403-407; Czaran TL, Hoekstra RF, Pagie L. 2002. Chemical warfare between microbes promotes biodiversity. Proc Natl Acad Sci U S A. 99(2):786-790; Cascales E, Buchanan SK, Duche D, Kleanthous C, Lloubes R, Postle K, Riley M, Slatin S, Cavard D. 2007. Colicin biology. Microbiol Mol Biol Rev. 71(1):158-229). By systematically assessing the distribution of fitness effects of similar to 9,000 single amino acid replacements in TolC using either positive (antibiotics and bile salts) or negative (colicin E1 and TLS phage) selection pressures, we quantified evolvability of the TolC. We demonstrated that the TolC is highly optimized for the efflux of antibiotics and bile salts. In contrast, under colicin E1 and TLS phage selection, TolC sequence is very sensitive to mutations. Finally, we have identified a large set of mutations in TolC that increase resistance of E. coli against colicin E1 or TLS phage without changing antibiotic susceptibility of bacterial cells. Our findings suggest that TolC is a highly evolvable target under negative selection which may limit the potential clinical use of bacteriophages and bacterial toxins if evolutionary aspects are not taken into account.
引用
收藏
页码:4493 / 4504
页数:12
相关论文
共 1 条
  • [1] The major E-coli MDR efflux pump AcrAB-TolC does not require AcrZ protein for expelling the novel highly effective antibiotic SkQ1 out of bacterial cells
    Nazarov, P.
    Korzina, A.
    Kotova, E.
    Antonenko, Y.
    FEBS JOURNAL, 2017, 284 : 160 - 160