Resistance to the tetracyclines and macrolide-lincosamide-streptogramin group of antibiotics and its genetic linkage – a review
More details
Hide details
Bavarian Health Food Safety Authority, 85764 Oberschleißheim, Germany
Durdica Marosevic   

Bavarian Health Food Safety Authority, 85764 Oberschleißheim, Germany
Ann Agric Environ Med. 2017;24(2):338–344
An excessive use of antimicrobial agents poses a risk for the selection of resistant bacteria. Of particular interest are antibiotics that have large consumption rates in both veterinary and human medicine, such as the tetracyclines and macrolide-lincosamide-streptogramin (MLS) group of antibiotics. A high load of these agents increases the risk of transmission of resistant bacteria and/or resistance determinants to humans, leading to a subsequent therapeutic failure. An increasing incidence of bacteria resistant to both tetracyclines and MLS antibiotics has been recently observed. This review summarizes the current knowledge on different tetracycline and MLS resistance genes that can be linked together on transposable elements.
European Centre for Disease Prevention and Control. Surveillance of antimicrobial consumption in europe 2012. 2014.
European Medicines Agency ESOVaC. Sales of veterinary antimicrobial agents in 26 eu/eea countries in 2012. 2014.
Chopra I, Hawkey PM, Hinton M. Tetracyclines, molecular and clinical aspects. J Antimicrob Chemother. 1992; 29: 245–277.
Shoemaker NB, Vlamakis H, Hayes K, Salyers AA. Evidence for extensive resistance gene transfer among Bacteroides spp. and among Bacteroides and other genera in the human colon. Appl Environ Microbiol. 2001; 67: 561–568.
Garcia-Migura L, Hendriksen RS, Fraile L, Aarestrup FM. Antimicrobial resistance of zoonotic and commensal bacteria in europe: The missing link between consumption and resistance in veterinary medicine. Vet Microbiol. 2014; 170: 1–9.
Cabello FC, Godfrey HP, Tomova A, Ivanova L, Dölz H, Millanao A, Buschmann AH. Antimicrobial use in aquaculture re-examined: Its relevance to antimicrobial resistance and to animal and human health. Environ Microbiol. 2013; 15: 1917–1942.
Duffy B, Holliger E, Walsh F. Streptomycin use in apple orchards did not increase abundance of mobile resistance genes. FEMS Microbiol Lett. 2014; 350: 180–189.
Nguyen F, Starosta AL, Arenz S, Sohmen D, Donhofer A, Wilson DN. Tetracycline antibiotics and resistance mechanisms. Biological chemistry. 2014; 395: 559–575.
Roberts MC. Mechanism of resistance for characterized tet and otr genes. http://faculty.Washington.Edu/... (modified: July 2016; date accessed: December 2016).
Poulsen SM, Kofoed C, Vester B. Inhibition of the ribosomal peptidyl transferase reaction by the mycarose moiety of the antibiotics carbomycin, spiramycin and tylosin. J Mol Biol. 2000; 304: 471–481.
Cocito C, Di Giambattista M, Nyssen E, Vannuffel P. Inhibition of protein synthesis by streptogramins and related antibiotics. Antimicrob Agents Chemother. 1997; 39 Suppl A, 7–13.
Hraoui M, Boutiba-Ben Boubaker I, Rachdi M, Slim A, Ben Redjeb S. Macrolide and tetracycline resistance in clinical strains of Streptococcus agalactiae isolated in Tunisia. J Med Microbiol. 2012; 61: 1109–1113.
Marimon JM, Valiente A, Ercibengoa M, García-Arenzana JM, Perez-Trallero E. Erythromycin resistance and genetic elements carrying macrolide efflux genes in Streptococcus agalactiae. Antimicrob Agents Chemother. 2005; 49: 5069–5074.
Roberts MC. Mechanisms of mls resistance (including nonpublished). http://faculty.Washington. Edu/marilynr/ermweba.Pdf (modified: July 2016; date accessed: December2016).
Aminov RI. Biotic acts of antibiotics. Frontiers in Microbiology. 2013; 4: 241.
European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2014. 2015.
Rodriguez-Avial I, Rodriguez-Avial C, Culebras E, Picazo JJ. Distribution of tetracycline resistance genes tet(m), tet(o), tet(l) and tet(k) in blood isolates of viridans group streptococci harbouring erm(b) and mef(a) genes. Susceptibility to quinupristin/dalfopristin and linezolid. Int J Antimicrob Agents. 2003; 21: 536–541.
Seral C, Castillo FJ, Rubio-Calvo MC, Fenoll A, Garcia C, Gomez-Lus R. Distribution of resistance genes tet(m), aph3 ‘-iii, cat(pc194) and the integrase gene of Tn1545 in clinical Streptococcus pneumoniae harbouring erm(b) and mef(a) genes in Spain. J Antimicrob Chemother. 2001; 47: 863–866.
Roberts AP, Mullany P. Tn916-like genetic elements: A diverse group of modular mobile elements conferring antibiotic resistance. FEMS Microbiol Rev. 2011; 35: 856–871.
Del Grosso M, Scotto D’abusco A, Iannelli F, Pozzi G, Pantosti A. Tn2009, a Tn916-like element containing mef(e) in Streptococcus pneumoniae. Antimicrob Agents Chemother. 2004; 48: 2037–2042.
Li Y, Tomita H, Lv Y, Liu J, Xue F, Zheng B, Ike Y. Molecular characterization of erm(b)- and mef(e)-mediated erythromycin-resistant Streptococcus pneumoniae in China and complete DNA sequence of Tn2010. J Appl Microbiol. 2011; 110: 254–265.
Roberts MC. Update on macrolide–lincosamide–streptogramin, ketolide, and oxazolidinone resistance genes. FEMS Microbiol Lett. 2008; 282: 147–159.
Franke AE, Clewell DB. Evidence for a chromosome-borne resistance transposon (Tn916) in Streptococcus faecalis that is capable of “conjugal” transfer in the absence of a conjugative plasmid. J Bacteriol. 1981; 145: 494–502.
Santoro F, Vianna ME, Roberts AP. Variation on a theme; an overview of the Tn916/Tn1545 family of mobile genetic elements in the oral and nasopharyngeal streptococci. Antimicrobials, Resistance and Chemotherapy. 2014; 5: 535.
Johnsen PJ, Townsend JP, Bohn T, Simonsen GS, Sundsfjord A, Nielsen KM. Factors affecting the reversal of antimicrobial-drug resistance. Lancet Infectious Diseases. 2009; 9: 357–364.
Shaw JH, Clewell DB. Complete nucleotide sequence of macrolide-lincosamide-streptogramin b-resistance transposon Tn917 in Streptococcus faecalis. J Bacteriol. 1985; 164: 782–796.
Del Grosso M, Camilli R, Iannelli F, Pozzi G, Pantosti A. The mef(e)-carrying genetic element (mega) of Streptococcus pneumoniae: Insertion sites and association with other genetic elements. Antimicrob Agents Chemother. 2006; 50: 3361–3366.
Poyartsalmeron C, Trieucuot P, Carlier C, Courvalin P. Nucleotide-sequences specific for Tn 1545-like conjugative transposons in pneumococci and staphylococci resistant to tetracycline. Antimicrob Agents Chemother. 1991; 35: 1657–1660.
Rice LB, Carias LL. Transfer of Tn5385, a composite, multiresistance chromosomal element from Enterococcus faecalis. J Bacteriol. 1998; 180: 714–721.
Cochetti I, Tili E, Mingoia M, Varaldo PE, Montanari MP.Erm(b)-carrying elements in tetracycline-resistant pneumococci and correspondence between Tn1545 and Tn6003. Antimicrob Agents Chemother. 2008; 52: 1285–1290.
De Vries LE, Valles Y, Agerso Y, Vaishampayan PA, Garcia-Montaner A, Kuehl JV, Christensen H, Barlow M, Francino MP. The gut as reservoir of antibiotic resistance: Microbial diversity of tetracycline resistance in mother and infant. PLoS ONE. 2011; 6, e21644.
Palmieri C, Mingoia M, Massidda O, Giovanetti E, Varaldoa PE. Strepto coccus pneumoniae transposon Tn1545/Tn6003 changes to Tn6002 due to spontaneous excision in circular form of the erm(b)-and apha3-containing macrolide-aminoglycoside-streptothricin (mas) element. Antimicrob Agents Chemother. 2012; 56: 5994–5997.
Warburton PJ, Palmer RM, Munson MA, Wade WG. Demonstration of in vivo transfer of doxycycline resistance mediated by a novel transposon. J Antimicrob Chemother. 2007; 60: 973–980.
Whittle G, Hund BD, Shoemaker NB, Salyers AA. Characterization of the 13-kilobase erm(f) region of the bacteroides conjugative transposon CTNDOT. Appl Environ Microbiol. 2001; 67: 3488–3495.
Gupta A, Vlamakis H, Shoemaker N, Salyers AA. A new bacteroides conjugative transposon that carries an erm(b) gene. Appl Environ Microbiol. 2003; 69: 6455–6463.
Moore IF, Hughes DW, Wright GD. Tigecycline is modified by the flavin-dependent monooxygenase tet(x). Biochemistry. 2005; 44: 11829–11835.
Aminov RI. Evolution in action: Dissemination of tet(x) into pathogenic microbiota. Frontiers in Microbiology. 2013; 4.
Leski TA, Bangura U, Jimmy DH, Ansumana R, Lizewski SE, Stenger DA, Taitt CR, Vora GJ. Multidrug-resistant tet(x)-containing hospital isolates in Sierra Leone. Int J Antimicrob Agents. 2013; 42: 83–86.
Del Grosso M, Camilli R, Libisch B, Fuzi M, Pantosti A. New composite genetic element of the tn916 family with dual macrolide resistance genes in a streptococcus pneumoniae isolate belonging to clonal complex 271. Antimicrob Agents Chemother. 2009; 53: 1293–1294.
Brenciani A, Bacciaglia A, Vecchi M, Vitali LA, Varaldo PE, Giovanettil E. Genetic elements carrying erm(b) in Streptococcus pyogenes and association with tet(m) tetracycline resistance gene. Antimicrob Agents Chemother. 2007; 51: 1209–1216.
Cochetti I, Tili E, Vecchi M, Manzin A, Mingoia M, Varaldo PE, Montanari MP. New Tn916-related elements causing erm(b)-mediated erythromycin resistance in tetracycline-susceptible pneumococci. J Antimicrob Chemother. 2007; 60: 127–131.
Santoro F, Oggioni MR, Pozzi G, Iannelli F. Nucleotide sequence and functional analysis of the tet (m)-carrying conjugative transposon Tn5251 of Streptococcus pneumoniae. FEMS Microbiol Lett. 2010; 308: 150–158.
Mingoia M, Tili E, Manso E, Varaldo PE, Montanari MP. Heterogeneity of Tn5253-like composite elements in clinical Streptococcus pneumoniae isolates. Antimicrob Agents Chemother. 2011; 55: 1453–1459.
Giovanetti E, Brenciani A, Tiberi E, Bacciaglia A, Varaldo PE. ICESP2905, the erm(tr)-tet(o) element of Streptococcus pyogenes, is formed by two independent integrative and conjugative elements. Antimicrob Agents Chemother. 2012; 56: 591–594.
Giovanetti E, Brenciani A, Lupidi R, Roberts MC, Varaldo PE. Presence of the tet(o) gene in erythromycin- and tetracycline-resistant strains of Streptococcus pyogenes and linkage with either the mef(a) or the erm(a) gene. Antimicrob Agents Chemother. 2003; 47: 2844–2849.
Brenciani A, Bacciaglia A, Vignaroli C, Pugnaloni A, Varaldo PE, Giovanetti E. Phi m46.1, the main Streptococcus pyogenes element carrying mef(a) and tet(o) genes. Antimicrob Agents Chemother. 2010; 54: 221–229.
Martel A, Decostere A, Leener ED, Marien M, Graef ED, Heyndrickx M, Goossens H, Lammens C, Devriese LA, Haesebrouck F. Comparison and transferability of the erm(b) genes between human and farm animal streptococci. Microbial Drug Resistance. 2005; 11: 295–302.
Vignaroli C, Zandri G, Aquilanti L, Pasquaroli S, Biavasco F. Multidrug-resistant enterococci in animal meat and faeces and co-transfer of resistance from an Enterococcus durans to a human Enterococcus faecium. Curr Microbiol. 2011; 62: 1438–1447.
Jasni AS, Mullany P, Hussain H, Roberts AP. Demonstration of conjugative transposon (Tn5397)-mediated horizontal gene transfer between Clostridium difficile and Enterococcus faecalis. Antimicrob Agents Chemother. 2010; 54: 4924–4926.
Wasels F, Monot M, Spigaglia P, Barbanti F, Ma L, Bouchier C, Dupuy B, Mastrantonio P. Inter- and intraspecies transfer of a Clostridium difficile conjugative transposon conferring resistance to MLS B . Microbial Drug Resistance. 2014; 20: 555–560.
Florez AB, Ammor MS, Mayo B. Identification of tet(m) in two Lactococcus lactis strains isolated from a spanish traditional starter-free cheese made of raw milk and conjugative transfer of tetracycline resistance to lactococci and enterococci. Int J Food Microbiol. 2008; 121: 189–194.
Rizzotti L, La Gioia F, Dellaglio F, Torriani S. Molecular diversity and transferability of the tetracycline resistance gene tet(m), carried on Tn916–1545 family transposons, in enterococci from a total food chain. Antonie Van Leeuwenhoek International Journal of General and Molecular Microbiology. 2009; 96: 43–52.
Gazzola S, Fontana C, Bassi D, Cocconcelli PS. Assessment of tetracycline and erythromycin resistance transfer during sausage fermentation by culture-dependent and -independent methods. Food Microbiol. 2012; 30: 348–354.
Cocconcelli PS, Cattivelli D, Gazzola S. Gene transfer of vancomycin and tetracycline resistances among Enterococcus faecalis during cheese and sausage fermentations. Int J Food Microbiol. 2003; 88: 315–323.
Gevers D, Huys G, Swings J. In vitro conjugal transfer of tetracycline resistance from Lactobacillus isolates to other gram-positive bacteria. FEMS Microbiol Lett. 2003; 225: 125–130.
Ojo KK, Ruehlen NL, Close NS, Luis H, Bernardo M, Leitao J, Roberts MC. The presence of a conjugative gram-positive Tn 2009 in gram-negative commensal bacteria. J Antimicrob Chemother. 2006; 57: 1065–1069.
Iannelli F, Santoro F, Oggioni MR, Pozzi G. Nucleotide sequence analysis of integrative conjugative element Tn5253 of Streptococcus pneumoniae. Antimicrob Agents Chemother. 2014; 58: 1235–1239.
Boguslawska J, Zycka-Krzesinska J, Wilcks A, Bardowski J. Intra- and interspecies conjugal transfer of Tn916-like elements from Lactococcus lactis in vitro and in vivo. Appl Environ Microbiol. 2009; 75: 6352–6360.
McCarthy AJ, Loeffler A, Witney AA, Gould KA, Lloyd DH, Lindsay JA. Extensive horizontal gene transfer during Staphylococcus aureus co-colonization in vivo. Genome Biology and Evolution. 2014; 6: 2697–2708.
Moubareck C, Bourgeois N, Courvalin P, Doucet-Populaire F. Multiple antibiotic resistance gene transfer from animal to human enterococci in the digestive tract of gnotobiotic mice. Antimicrob Agents Chemother. 2003; 47: 2993–2996.
Doucet-Populaire F, Trieu-Cuot P, Dosbaa I, Andremont A, Courvalin P. Inducible transfer of conjugative transposon Tn1545 from Enterococcus faecalis to Listeria monocytogenes in the digestive tracts of gnotobiotic mice. Antimicrob Agents Chemother. 1991; 35: 185–187.
Jacobsen L, Wilcks A, Hammer K, Huys G, Gevers D, Andersen SR. Horizontal transfer of tet(m) and erm(b) resistance plasmids from food strains of Lactobacillus plantarum to Enterococcus faecalis jh2–2 in the gastrointestinal tract of gnotobiotic rats. FEMS Microbiol Ecol. 2007; 59: 158–166.
Marosevic D, Cervinkova D, Vlkova H, Videnska P, Babak V, Jaglic Z. In vivo spread of macrolide-lincosamide-streptogramin B (MLS B ) resistance-a model study in chickens. Vet Microbiol. 2014; 171: 388–396.
De Leener E, Martel A, Decostere A, Haesebrouck F. Distribution of the erm (b) gene, tetracycline resistance genes, and Tn1545-like transposons in macrolide- and lincosamide-resistant enterococci from pigs and humans. Microbial Drug Resistance-Mechanisms Epidemiology and Disease. 2004; 10: 341–345.
Sorensen TL, Blom M, Monnet DL, Frimodt-Moller N, Poulsen RL, Espersen F. Transient intestinal carriage after ingestion of antibiotic-resistant Enterococcus faecium from chicken and pork. New England Journal of Medicine. 2001; 345: 1161–1166.