Margo Lee, Ph.D.
Bacterial organisms coexist as multispecies communities in nature. These communities can range from a couple of bacteria to millions of microorganisms assembled in a complex, dynamic environment. Many species in these communities must interact to ensure survival in changing conditions, such as their physical environment, metabolic and physiological variations, and competition within and outside their community members. Bacteria species interact and communicate with each other to ensure adaptation and survival to the changing conditions they will face, including the presence of antibiotics.
Polymicrobial Infections can occur in many areas of the body and are identified in up to 52% of all urinary tract infections (UTI).1 Both monomial and polymicrobial UTI infections can produce symptoms such as increased urgency and frequency with painful urination. Some bacteria commonly involved in UTI infections are Escherichia coli, Klebsiella pneumonia, Proteus mirabilis, and Enterococcus faecalis but may also include yeast and fungi.
Transfer of Antibiotic Resistance Genes
Resistant pathogens may share their antibiotic resistance (ABR) genes with susceptible species through sharing of plasmid DNA. Bacteria in close contact with one another can use horizontal gene transfer through direct cell contact or associations with transposons to transfer mobile genetic elements (MGEs) that contain one or more antibiotic resistance genes to a susceptible bacteria in the community.2 Bacteria share DNA plasmids through conjugation, where DNA from a donor cell is transferred to a recipient cell.3 Transposons can also help move DNA from one cell to another and insert elements into promoter regions that enhance gene expression of ABR genes downstream of these insertion sites. These interactions can be complex, occur between many different species (such as between gram negative and gram-positive bacteria), and involve genes that encode resistance for beta-lactams, macrolides, quinolones, sulphonamides, and tetracyclines.4 The transfer of these mobile genetic elements is one of the driving forces between multiresistant bacteria and the rise of healthcare-associated bacterial infections.5
Cooperative Interactions of UTI Pathogens
Another example of communication between bacteria in polymicrobial UTI infections is the urease activity of Proteus mirabilis and many bacterial species. Urease, a nickel metalloenzyme, is an essential factor in the virulence of Proteus mirabilis which catalyzes the hydrolysis of urea to carbon dioxide and ammonia, leading to the formation of urinary stones. The levels of urease activity by P. mirabilis are increased in the presence of many other species, such as Escherichia coli,6 Providencia stuartii,7 Enterococcus faecalis,8 Klebsiella pneumoniae,9 or Pseudomonas aeruginosa.10 Proteus mirabilis and these species of bacteria are frequently found in complicated, reoccurring UTI infections and interact with each other to increase urease activity, struvite and apatite crystal formation, crystalline biofilms, and increased pathogenicity.11
Bacterial Inactivation of Antibiotics
Resistant bacteria can also decrease an antibiotic’s effectiveness and help other susceptible bacteria survive in its presence. There are many ways bacteria can reduce or inactivate antibiotics, such as
enzymatic alteration of the antibiotic (acetyltransferase (ACC), adenyltransferase (ANT) and phosphotransferase (APH), the destruction of the antibiotic by the action of β- lactamases, and
decreased antibiotic permeability, antibiotic efflux pumps, and interference by modifying the target site of the antibiotic.12 In each of these examples, bacteria can alter the antibiotic or their response to an antibiotic to make them resistant to antibiotics.13
Guidance® UTI testing captures these polymicrobial interactions between species to understand the antibiotic susceptibility of the infection. Physicians should evaluate bacteria communities by using the comprehensive pooled pathogens susceptibility test ( P-AST™) in a UTI to capture all these bacterial interactions that can modify antibiotic susceptibility. Standard urine culture (SUC) can identify one or two pathogens individually at a time and will not capture these vital bacterial interactions that can impact the susceptibility.1
Pooled Antibiotic Susceptibility testing or P-AST™ is a patented technology included in Guidance® UTI testing. Guidance® UTI combines pathogen identification and antibiotic resistance gene detection by multiplex polymerase chain reaction (PCR) together with Pooled Antibiotic Susceptibility Testing (PAST™) that evaluates the infection in the presence of 19 antibiotics that are frequently prescribed to treat chronic, reoccurring diseases and delivers a comprehensive guide to antibiotic selection specifically tailored to the patient’s illness.
1 Vollstedt A, Baunoch D, Wojno KJ, Luke N, Cline K, et al. (2020). Multisite Prospective Comparison of Multiplex Polymerase Chain Reaction Testing with Urine Culture for Diagnosis of Urinary Tract Infections in Symptomatic Patients. J Sur urology, JSU-102. DOI: 10.29011/ JSU-102.100002
2 Yao, Y., Maddamsetti, R., Weiss, A. et al. Intra- and interpopulation transposition of mobile genetic elements driven by antibiotic selection. Nat Ecol Evol 6, 555–564 (2022). https://doi.org/10.1038/s41559-022-01705-2
3 Graf FE, Palm M, Warringer J, Farewell A. Inhibiting conjugation as a tool in the fight against antibiotic resistance. Drug Dev Res. 2019
Feb;80(1):19-23. doi: 10.1002/ddr.21457. Epub 2018 Oct 21. PMID: 30343487.
4 Partridge SR, Kwong SM, Firth N, Jensen SO. Mobile Genetic Elements Associated with Antimicrobial Resistance. Clin Microbiol Rev. 2018 Aug 1;31(4):e00088-17. doi: 10.1128/CMR.00088-17. PMID: 30068738; PMCID: PMC6148190.
5 Babakhani S, Oloomi M. Transposons: the agents of antibiotic resistance in bacteria. J Basic Microbiol. 2018 Nov;58(11):905-917. doi: 10.1002/jobm.201800204. Epub 2018 Aug 16. PMID: 30113080.
6 Jones BD, Mobley HL. Proteus mirabilis urease: genetic organization, regulation, and expression of structural genes. J Bacteriol. 1988 Aug;170(8):3342-9. doi: 10.1128/jb.170.8.3342-3349.1988. PMID: 2841283; PMCID: PMC211300.
7 Armbruster CE, Smith SN, Yep A, Mobley HL. Increased incidence of urolithiasis and bacteremia during Proteus mirabilis and Providencia stuartii coinfection due to synergistic induction of urease activity. J Infect Dis. 2014 May 15;209(10):1524-32. doi: 10.1093/infdis/jit663. Epub 2013 Nov 26. PMID: 24280366; PMCID: PMC3997575.
8 Learman BS, Brauer AL, Eaton KA, Armbruster CE. A Rare Opportunist, Morganella morganii, Decreases Severity of Polymicrobial Catheter-Associated Urinary Tract Infection. Infect Immun. 2019 Dec 17;88(1):e00691-19. doi: 10.1128/IAI.00691-19. PMID: 31611275; PMCID: PMC6921659.
9 Palusiak A. Proteus mirabilis and Klebsiella pneumoniae as pathogens capable of causing co-infections and exhibiting similarities in their virulence factors. Front Cell Infect Microbiol. 2022 Oct 20;12:991657. doi: 10.3389/fcimb.2022.991657. PMID: 36339335; PMCID: PMC9630907.
10 Xiaobao Li, Nanxi Lu, Hannah R. Brady, Aaron I. Packman, Biomineralization strongly modulates the formation of Proteus
mirabilis and Pseudomonas aeruginosa dual-species biofilms, FEMS Microbiology Ecology, Volume 92, Issue 12, December 2016,
11 Sriwanthana B, Island MD, Maneval D, Mobley HL. Single-step purification of Proteus mirabilis urease accessory protein UreE, a protein with a naturally occurring histidine tail, by nickel chelate affinity chromatography. J Bacteriol. 1994 Nov;176(22):6836-41. doi: 10.1128/jb.176.22.6836- 6841.1994. PMID: 7961442; PMCID: PMC197051.
12 Munita JM, Arias CA. Mechanisms of Antibiotic Resistance. Microbiol Spectr. 2016 Apr;4(2):10.1128/microbiolspec.VMBF-0016-2015. doi: 10.1128/microbiolspec.VMBF-0016-2015. PMID: 27227291; PMCID: PMC4888801.
13 Darby, E.M., Trampari, E., Siasat, P. et al. Molecular mechanisms of antibiotic resistance revisited. Nat Rev Microbiol (2022).