Genetics of Acquired Antibiotic Resistance Genes in Proteus spp

Abstract

Proteus spp. are commensal Enterobacterales of the human digestive tract. At the same time, P. mirabilis is commonly involved in urinary tract infections (UTI). P. mirabilis is naturally resistant to several antibiotics including colistin and shows reduced susceptibility to imipenem. However higher levels of resistance to imipenem commonly occur in P. mirabilis isolates consecutively to the loss of porins, reduced expression of penicillin binding proteins (PBPs) PBP1a, PBP2, or acquisition of several antibiotic resistance genes, including carbapenemase genes. In addition, resistance to non-β-lactams is also frequently reported including molecules used for treating UTI infections (e.g., fluoroquinolones, nitrofurans). Emergence and spread of multidrug resistant P. mirabilis isolates, including those producing ESBLs, AmpC cephalosporinases and carbapenemases, are being more and more frequently reported. This review covers Proteus spp. with a focus on the different genetic mechanisms involved in the acquisition of resistance genes to multiple antibiotic classes turning P. mirabilis into a dreadful pandrug resistant bacteria and resulting in difficult to treat infections.

Keywords: ESBL; Proteus mirabilis; beta-lactamase; carbapenemase; urinary tract infections.

FIGURE 1

Antibiogram of wild-type Proteus mirabilis CIP103181 (A), inhibitors resistant TEM (IRT)- TEM-67-producing P. mirabilis NEL (Naas et al., 2003) (B), ESBL producing P. mirabilis LIL-1 (Naas et al., 2000) (C), plasmid-encoded cephalosporinase ACC-1 producing P. mirabilis SPI (Girlich et al., 2000a) (D), carbapenemase NDM-1 and ESBL VEB-6 producing P. mirabilis PEL (Girlich et al., 2015) (E), Carbapenem hydrolyzing oxacillinases (CHDL) OXA-58-producing P. mirabilis 1091 (Girlich et al., 2017) (F). β-Lactam abbreviations (from left to right and top to bottom): TZP, piperacillin-tazobactam; PIP, piperacillin; TIC, ticarcillin; AMX, amoxicillin; ETP, ertapenem; TCC, ticarcillin-clavulanic acid; CAZ, ceftazidime; TEM, temocillin; FOX, cefoxitin, IMP, imipenem; AMC, amoxicillin-clavulanic acid; CTX, cefotaxime; MOX, moxalactam; MEM, meropenem; ATM, aztreonam; FEP, cefepime. Non-β-lactam abbreviations (from left to right and from top to bottom): FOS, fosfomycin; COL, colistin; NET, netilmicin; TET, tetracycline, OFX, ofloxacin; TGC, tigecycline; CIP, ciprofloxacin; TOB, tobramicine; LEV, levofloxacin; RIF, rifampicin; SXT, trimethoprim-sulfamethoxazole; AMK, amikacin; NOR, norfloxacin; MEL, Mecillinam; NF, nitrofurantoin, GEN, gentamycin.

FIGURE 2

Schematic representation of the structure containing (A) the qnrD gene in P. rettgeri pDIJ09-518a on a non-transmissible plasmid, the right (IRR) and left (IRL) repeated inverted sequences also named “mobile insertion cassette” elements (mic), used for mobilization of qnrD, are indicated by black triangles (Guillard et al., 2014); (B) the bla_TEM–67 gene in Tn1 flanked by two IS26 on the non-transferable plasmid of P. mirabilis NEL (Naas et al., 2003); (C) the bla_CMY gene within the ISEcp1: Tn6093 transposition module inserted into the pepQ gene of P. mirabilis (D’Andrea et al., 2006); (D) the bla_CMY–2 gene inserted into ICE R391 from P. mirabilis PmiJpn1 (Harada et al., 2010); (E) the bla_CTX–M–2 gene located on the chromosomes of P. mirabilis TUM4657 (Harada et al., 2012), the 5 letters correspond to the direct repeat sequences (DRL and DRR). The β-lactamase genes and their orientation are represented by black arrows and the IS by black triangles, including the IR-R and IR-L of ISEcp1 and the IR-R of the ISEcp1 transposition unit.

FIGURE 3

Genetic environments of β-lactamase genes identified in P. mirabilis. (A) Fragment 3,241 pb from P. mirabilis, China, 2015 (Hu et al., 2012), containing bla_KPC–2, ISKpn8 and ISKpn6-like, chimera of several elements of transposons Tn4401 and Tn3, as described for K. pneumoniae KP048 (Shen et al., 2009); (B) plasmid fragment from OXA-48 and CTX-M-14 -producing P. mirabilis, Gaza, Palestine (Chen et al., 2015); (C) PGI1-PmPEL genomic island, France, 2016 (Girlich et al., 2015), with the multidrug resistance region (MDR) containing the bla_NDM–1 and bla_VEB–6 (D) genes and comparison with SGI1-V from P. mirabilis, France, 2009 (Siebor and Neuwirth, 2011), containing a 17,1 kb MDR on a complex class 1 integron, including bla_VEB–6, aacA4, aadB and dhfrA1 genes bracketed by two 3′ conserved segments (3′-CS); (E) chromosomal fragment from P. mirabilis 1091 isolate, Belgium, 2017 (Girlich et al., 2017), containing bla_OXA–58 [from A. baumannii (Bonnin et al., 2013b)] and bla_AmpC (from an uncultured bacterium, GenBank N°AMP47568) genes, related to Acinetobacter bohemicus (GenBank N° WP_004650432). Triangles represent tandem repeats of 14-pb. The β-lactamase genes and their orientation are represented by black arrows and ISs by black triangles.