Antibiotic resistance in gonorrhea

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Gram stain of Neisseria gonorrhoeae showing characteristic diplococci morphology NeisseriaGonorrhoeae.jpg
Gram stain of Neisseria gonorrhoeae showing characteristic diplococci morphology

Neisseria gonorrhoeae , the bacterium that causes the sexually transmitted infection gonorrhea, has developed antibiotic resistance to many antibiotics. The bacteria was first identified in 1879. [1]

Contents

In the 1940s effective treatment with penicillin became available, but by the 1970s resistant strains predominated. Resistance to penicillin has developed through two mechanisms: chromosomally mediated resistance (CMRNG) and penicillinase-mediated resistance (PPNG). CMRNG involves step wise mutation of penA, which codes for the penicillin-binding protein (PBP-2); mtr, which encodes an efflux pump that removes penicillin from the cell; and penB, which encodes the bacterial cell wall porins. PPNG involves the acquisition of a plasmid-borne beta-lactamase. [2] N. gonorrhoeae has a high affinity for horizontal gene transfer, and as a result, the existence of any strain resistant to a given drug could spread easily across strains.[ citation needed ]

Cases of Neisseria Gonorrhoeae with decreased susceptibility or resistance to antibiotics (2017-2018). Cases of Neisseria Gonorrhoeae with decreased susceptibility or resistance to antibiotics (2017-2018).svg
Cases of Neisseria Gonorrhoeae with decreased susceptibility or resistance to antibiotics (2017-2018).

Fluoroquinolones were a useful next-line treatment until resistance was achieved through efflux pumps and mutations to the gyrA gene, which encodes DNA gyrase. [2] Third-generation cephalosporins have been used to treat gonorrhoea since 2007, but resistant strains have emerged. As of 2010, the recommended treatment is a single 250 mg intramuscular injection of ceftriaxone, sometimes in combination with azithromycin or doxycycline. [3] [4] However, certain strains of N. gonorrhoeae can be resistant to antibiotics that are normally used to treat it. These include: cefixime (an oral cephalosporin), ceftriaxone (an injectable cephalosporin), azithromycin, aminoglycosides, and tetracycline. [5] [6]

Penicillins

Old advertisement for penicillin treatment Penicillin cures gonorrhea.jpg
Old advertisement for penicillin treatment

Beta-lactams like penicillin were widely used to treat gonorrhea in the 1940s. There are three general mechanisms that may allow bacteria to become resistant to beta-lactam antibiotics:

  1. inability to access/target penicillin-binding protein (PBP) enzyme
  2. inhibition of binding to PBP via modification of the enzyme
  3. hydrolysis/inactivation of the antibiotic by beta-lactamases. [7]

Overuse of penicillin contributed to Neisseria gonorrhoeae developing high resistance to penicillin through two main mechanisms: chromosomally mediated resistance (CMRNG) and penicillinase-mediated resistance (PPNG). [2]

Chromosomally mediated resistance occurred through step-wise changes over many years. Chromosomal mutations in the penA, mtr, and penB genes are the major mechanisms for CMRNG. The penA gene encodes an alternative penicillin-binding protein, PBP-2. [2] This mechanism falls under the second general mechanism for beta-lactam resistance. PBPs, also known as transpeptidases, are targets for beta-lactams. These enzymes (PBPs) are involved in peptidoglycan synthesis which is a major component of the bacterial cell wall. PBPs cross-link the amino acid strands of peptidoglycan during synthesis. Normally, beta-lactams bind the PBPs and thereby inhibit the cross-linking of peptidoglycan. When this occurs, the cell wall of the bacterium is compromised and often results in cell death. [7] When N. gonorrhoeae encodes penA, the new PBP-2 that is synthesized is no longer recognized by the beta-lactams rendering the bacterium resistant.[ citation needed ]

The mtr (multiple transferable resistance) gene encodes for an efflux pump. [8] Efflux pumps mediate resistance to a variety of compounds including antibiotics, detergents, and dyes. [2] This mechanism falls under the first general resistance mechanism to beta-lactams. mtr encodes for the protein MtrD which is the efflux pump for N. gonorrhoeae. [2] MtrD is among the Resistance Nodulation Division (RND) efflux pump superfamily. These pumps are proton antiporters where the antibiotic is pumped out of the cell while a proton is pumped into the cell. [9]

The cell wall of N. gonorrhoeae contains porins which are holes within the cell wall in which some molecules are able to diffuse into or out of the cell membrane. This mechanism falls under the first general mechanism for beta-lactam resistance. The penB gene encodes the porins for N. gonorrhoeae and when this gene undergoes mutations, there is a decrease in permeability of the cell wall to hydrophilic antibiotics like penicillin. [2]

Penicillinase-mediated resistance in N. gonorrhoeae is mediated by the plasmid borne TEM-1 type beta-lactamase which falls under the third general mechanism for beta-lactam resistance. [2] There have been over 200 beta-lactamases described and some of them are antibiotic specific. [7] TEM-1 is a penicillinase specific for penicillins. This enzyme will bind to the beta-lactam ring which is a structural characteristic for beta-lactams and hydrolyze the ring. This renders the antibiotic inactive. The spread of the penicillinase resistance was much faster compared to the chromosomal-mediated resistance mechanisms. The plasmids containing TEM-1 could be passed from bacterium to bacterium via conjugation [2]

Quinolones

Quinolones are a class of synthetic antibiotics that inhibit DNA replication, recombination, and repair by interacting with the bacterial DNA gyrase and/or topoisomerase IV. [7] Second generation quinolones like ciprofloxacin and ofloxacin have been widely used to treat N. gonorrhoeae infections. Resistance to these antibiotics has developed over the years with chromosomal resistance being the primary mechanism. [2]

Low-level quinolone resistance has been linked to changes in cell permeability and efflux pumps. The NorM efflux pump is encoded by the norM gene and provides resistance to fluoroquinolones. [8] The NorM efflux pump is a member of the MATE (multidrug and toxic compound extrusion) family and functions by a Na+ antiporter. It is also known that a point mutation upstream of the norM gene will causes overexpression of NorM, and mediate elevated resistance. [8]

High-level resistance to quinolones has been seen through target modification acting on the DNA gyrase and topoisomerase IV. Multiple amino acid substation mutations in the gyrA gene, which encodes for the DNA gyrase, have been seen extensively. DNA gyrase is an enzyme that binds to DNA and introduces negative supercoiling. [10] This helps unwind the DNA for replication. If there is a mutation in the DNA gyrase, then the quinolone will not be able to bind to it resulting in the activity of DNA gyrase not being inhibited. Multiple mutations have also been noted in the parC gene which encodes for the topoisomerase IV. Topoisomerase IV acts similarly to DNA gyrase and is involved in unwinding DNA for replication. [10]

Cephalosporins

Basic structures of penicillins(1) and cephalosporins(2) with beta-lactam ring highlighted in red Beta-lactam antibiotics example 1.svg
Basic structures of penicillins(1) and cephalosporins(2) with beta-lactam ring highlighted in red

Ceftriaxone and cefixime are third generation cephalosporins and are often used as treatments for N. gonorrhoeae infections. [2] The cephalosporins are part of a larger beta-lactam family of antibiotics. [11] The newly discovered H041 strain of N. gonorrhoeae, originally isolated from a commercial sex worker in Japan, was shown to be resistant to this antibiotic. [12]

The possible mechanisms of resistance to this antibiotic are as follows:

  1. an alteration of more than four amino acids in the C-terminal end of the PBP-2, [13] which would result in the antibiotic being unable to bind to its target
  2. mutations in the promoter regions of mtr, resulting in the overexpression of genes that code for efflux pumps
  3. mutations in the penB gene that encodes for the bacterial porin. This form of resistance has only been observed with ceftriaxone which is administered through an intramuscular injection. [2]

Tetracyclines

Tetracyclines are a class of antibiotics that inhibit protein synthesis by binding to the 30s ribosomal subunit of bacterial cells, keeping transcription of the bacterial genome from occurring. [11] Tetracyclines are bacteriostatic, which means that the growth of the bacterium will be slowed. [7] Tetracyclines are not often recommended for the treatment of N. gonorrhoeae because the treatment regimen requires many doses, which may affect compliance and contribute to resistance. [2] Tetracycline is still used as treatment for this infection in developing countries because the cost for the drug is low [2]

As with the penicillin resistance, the penB (porin formation) and mtr (efflux pump formation) mutations mediate chromosomal resistance. These adaptations will also affect the ability of the antibiotic to get into, or stay in the bacterial cell. High level resistance of N. gonorrhoeae to tetracyclines was first reported in 1986 with the discovering of the tetM determinant. [2] The mechanism of resistance is still unknown.

Aminoglycosides

N. gonorrhoeae has also shown resistance to the aminoglycoside class of antibiotics. These antibiotics bind to the 16s rRNA of the 30S subunit of the bacterial ribosome, [11] thereby inhibiting mRNA translation and protein synthesis. Resistance appears to be acquired through porin-related mechanisms, much like the cephalosporin resistance mechanism. This mechanism would result in the access of the antibiotic to the bacterial cell being inhibited. There is a possibility of future enzymes (made by the bacterium) that will be able to denature and inactivate the aminoglycosides. [2]

See also

Related Research Articles

<span class="mw-page-title-main">Beta-lactamase</span> Class of enzymes

Beta-lactamases (β-lactamases) are enzymes produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems (ertapenem), although carbapenems are relatively resistant to beta-lactamase. Beta-lactamase provides antibiotic resistance by breaking the antibiotics' structure. These antibiotics all have a common element in their molecular structure: a four-atom ring known as a beta-lactam (β-lactam) ring. Through hydrolysis, the enzyme lactamase breaks the β-lactam ring open, deactivating the molecule's antibacterial properties.

<span class="mw-page-title-main">Penicillin</span> Group of antibiotics derived from Penicillium fungi

Penicillins are a group of β-lactam antibiotics originally obtained from Penicillium moulds, principally P. chrysogenum and P. rubens. Most penicillins in clinical use are synthesised by P. chrysogenum using deep tank fermentation and then purified. A number of natural penicillins have been discovered, but only two purified compounds are in clinical use: penicillin G and penicillin V. Penicillins were among the first medications to be effective against many bacterial infections caused by staphylococci and streptococci. They are still widely used today for various bacterial infections, though many types of bacteria have developed resistance following extensive use.

<span class="mw-page-title-main">Beta-lactam antibiotics</span> Class of broad-spectrum antibiotics

β-lactam antibiotics are antibiotics that contain a beta-lactam ring in their chemical structure. This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and carbacephems. Most β-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics. Until 2003, when measured by sales, more than half of all commercially available antibiotics in use were β-lactam compounds. The first β-lactam antibiotic discovered, penicillin, was isolated from a strain of Penicillium rubens.

<i>Neisseria gonorrhoeae</i> Species of bacterium

Neisseria gonorrhoeae, also known as gonococcus (singular) or gonococci (plural), is a species of Gram-negative diplococci bacteria isolated by Albert Neisser in 1879. It causes the sexually transmitted genitourinary infection gonorrhea as well as other forms of gonococcal disease including disseminated gonococcemia, septic arthritis, and gonococcal ophthalmia neonatorum.

<span class="mw-page-title-main">Drug resistance</span> Pathogen resistance to medications

Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, resistance has evolved. Antimicrobial resistance and antineoplastic resistance challenge clinical care and drive research. When an organism is resistant to more than one drug, it is said to be multidrug-resistant.

<i>Neisseria</i> Genus of bacteria

Neisseria is a large genus of bacteria that colonize the mucosal surfaces of many animals. Of the 11 species that colonize humans, only two are pathogens, N. meningitidis and N. gonorrhoeae.

<span class="mw-page-title-main">Ertapenem</span> Antibiotic medication

Ertapenem, sold under the brand name Invanz, is a carbapenem antibiotic medication used for the treatment of infections of the abdomen, the lungs, the upper part of the female reproductive system, and the diabetic foot.

<span class="mw-page-title-main">Methicillin</span> Antibiotic medication

Methicillin (USAN), also known as meticillin (INN), is a narrow-spectrum β-lactam antibiotic of the penicillin class.

<span class="mw-page-title-main">Cephalosporin</span> Class of pharmaceutical drugs

The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Acremonium, which was previously known as Cephalosporium.

<span class="mw-page-title-main">Ceftriaxone</span> Antibiotic medication

Ceftriaxone, sold under the brand name Rocephin, is a third-generation cephalosporin antibiotic used for the treatment of a number of bacterial infections. These include middle ear infections, endocarditis, meningitis, pneumonia, bone and joint infections, intra-abdominal infections, skin infections, urinary tract infections, gonorrhea, and pelvic inflammatory disease. It is also sometimes used before surgery and following a bite wound to try to prevent infection. Ceftriaxone can be given by injection into a vein or into a muscle.

<span class="mw-page-title-main">Cefuroxime axetil</span> Chemical compound

Cefuroxime axetil, sold under the brand name Ceftin among others, is a second generation oral cephalosporin antibiotic.

<span class="mw-page-title-main">Cefotaxime</span> Chemical compound

Cefotaxime is an antibiotic used to treat a number of bacterial infections in human, other animals and plant tissue culture. Specifically in humans it is used to treat joint infections, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, sepsis, gonorrhea, and cellulitis. It is given either by injection into a vein or muscle.

<span class="mw-page-title-main">Penicillin-binding proteins</span> Class of proteins

Penicillin-binding proteins (PBPs) are a group of proteins that are characterized by their affinity for and binding of penicillin. They are a normal constituent of many bacteria; the name just reflects the way by which the protein was discovered. All β-lactam antibiotics bind to PBPs, which are essential for bacterial cell wall synthesis. PBPs are members of a subgroup of enzymes called transpeptidases. Specifically, PBPs are DD-transpeptidases.

<span class="mw-page-title-main">Efflux pump</span> Protein complexes that move compounds, generally toxic, out of bacterial cells

An efflux pump is an active transporter in cells that moves out unwanted material. Efflux pumps are an important component in bacteria in their ability to remove antibiotics. The efflux could also be the movement of heavy metals, organic pollutants, plant-produced compounds, quorum sensing signals, bacterial metabolites and neurotransmitters. All microorganisms, with a few exceptions, have highly conserved DNA sequences in their genome that encode efflux pumps. Efflux pumps actively move substances out of a microorganism, in a process known as active efflux, which is a vital part of xenobiotic metabolism. This active efflux mechanism is responsible for various types of resistance to bacterial pathogens within bacterial species - the most concerning being antibiotic resistance because microorganisms can have adapted efflux pumps to divert toxins out of the cytoplasm and into extracellular media.

β-Lactamase inhibitor Drugs that inhibit β-Lactamase enzymes

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. In bacterial resistance to beta-lactam antibiotics, the bacteria have beta-lactamase which degrade the beta-lactam rings, rendering the antibiotic ineffective. However, with beta-lactamase inhibitors, these enzymes on the bacteria are inhibited, thus allowing the antibiotic to take effect. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

mecA is a gene found in bacterial cells which allows them to be resistant to antibiotics such as methicillin, penicillin and other penicillin-like antibiotics.

<span class="mw-page-title-main">Plasmid-mediated resistance</span> Antibiotic resistance caused by a plasmid

Plasmid-mediated resistance is the transfer of antibiotic resistance genes which are carried on plasmids. Plasmids possess mechanisms that ensure their independent replication as well as those that regulate their replication number and guarantee stable inheritance during cell division. By the conjugation process, they can stimulate lateral transfer between bacteria from various genera and kingdoms. Numerous plasmids contain addiction-inducing systems that are typically based on toxin-antitoxin factors and capable of killing daughter cells that don't inherit the plasmid during cell division. Plasmids often carry multiple antibiotic resistance genes, contributing to the spread of multidrug-resistance (MDR). Antibiotic resistance mediated by MDR plasmids severely limits the treatment options for the infections caused by Gram-negative bacteria, especially family Enterobacteriaceae. The global spread of MDR plasmids has been enhanced by selective pressure from antimicrobial medications used in medical facilities and when raising animals for food.

Cephalosporins are a broad class of bactericidal antibiotics that include the β-lactam ring and share a structural similarity and mechanism of action with other β-lactam antibiotics. The cephalosporins have the ability to kill bacteria by inhibiting essential steps in the bacterial cell wall synthesis which in the end results in osmotic lysis and death of the bacterial cell. Cephalosporins are widely used antibiotics because of their clinical efficiency and desirable safety profile.

Nitrocefin Chemical compound

Nitrocefin is a chromogenic cephalosporin substrate routinely used to detect the presence of beta-lactamase enzymes produced by various microbes. Beta-lactamase mediated resistance to beta-lactam antibiotics such as penicillin is a widespread mechanism of resistance for a number of bacteria including members of the family Enterobacteriaceae, a major group of enteric Gram-negative bacteria. Other methods for beta-lactamase detection exist including PCR; however, nitrocefin allows for rapid beta-lactamase detection using few materials and inexpensive equipment.

The p-aminobenzoyl-glutamate transporter(AbgT) family (TC# 2.A.68) is a family of transporter proteins belonging to the ion transporter (IT) superfamily. The AbgT family consists of the AbgT (YdaH; TC# 2.A.68.1.1) protein of E. coli and the MtrF drug exporter (TC# 2.A.68.1.2) of Neisseria gonorrhoeae. The former protein is apparently cryptic in wild-type cells, but when expressed on a high copy number plasmid, or when expressed at higher levels due to mutation, it appeared to allow uptake (Km = 123 nM; see Michaelis–Menten kinetics) and subsequent utilization of p-aminobenzoyl-glutamate as a source of p-aminobenzoate for p-aminobenzoate auxotrophs. p-Aminobenzoate is a constituent of and a precursor for the biosynthesis of folic acid. MtrF was annotated as a putative drug efflux pump.

References

  1. ↑ Ligon BL (2005). "Albert Ludwig Sigesmund Neisser: discoverer of the cause of gonorrhea". Semin Pediatr Infect Dis. 16 (4): 336–41. doi:10.1053/j.spid.2005.07.001. PMID   16210113.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Tapsall, John (2001). "Antimicrobial resistance in Neisseria gonorrhoeae". World Health Organization. hdl:10665/66963.
  3. ↑ Deguchi T, Nakane K, Yasuda M, Maeda S (September 2010). "Emergence and spread of drug resistant Neisseria gonorrhoeae". J. Urol. 184 (3): 851–8, quiz 1235. doi:10.1016/j.juro.2010.04.078. PMID   20643433.
  4. ↑ Centers for Disease Control Prevention (CDC). (Aug 10, 2012). "Update to CDC's Sexually Transmitted Diseases Treatment Guidelines, 2010: Oral Cephalosporins No Longer a Recommended Treatment for Gonococcal Infections". MMWR. Morbidity and Mortality Weekly Report. 61 (31): 590–4. PMID   22874837.
  5. ↑ "Biggest Threats - Antibiotic/Antimicrobial Resistance - CDC". www.cdc.gov. Retrieved 2016-05-05.
  6. ↑ Pleininge, Sonja (April 2022). "Extensively drug-resistant (XDR) Neisseria gonorrhoeae causing possible gonorrhoea treatment failure with ceftriaxone plus azithromycin in Austria, April 2022". Euro Surveillance. 27 (24). doi:10.2807/1560-7917.ES.2022.27.24.2200455. PMC   9205165 . PMID   35713023. S2CID   249747652.
  7. 1 2 3 4 5 Murray, Patrick R., Ken S. Rosenthal, and Michael A. Pfaller. Medical Microbiology. 6th ed. Philadelphia: Mosby/Elsevier, 2009. Print
  8. 1 2 3 Rouquette-Loughlin, Dunham, Kuhn, Balthazar, Shafer (2003) The NorM Efflux Pump of Neisseria gonorrhoeae and Neissera meningitidis Recognizes Antimicrobial Cationic Compounds. Journal of Bacteriology 185:1101–1106
  9. ↑ Van Bambeke, Balzi, Tulkens (2000) Antibiotic Efflux Pumps. Biochemical Pharmacology 60:457–470
  10. 1 2 Drlica, Zhao (1997) DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiology and Molecular Biology Reviews 61:377–392
  11. 1 2 3 Wilson, Brenda A., Abigail A. Salyers, Dixie D. Whitt, and Malcolm A. Winkler. Bacterial Pathogenesis: A Molecular Approach. 3rd ed. Washington DC: ASM Press, 2011. Print.
  12. ↑ Unemo, Golparian, Nicholas, Ohnishi, Gallay, Sednaoui (2011) High-Level Cefixime- and Ceftriaxone-Resistant Neisseria gonorrhoeae in France: Novel penA Mosaic Allele in a Successful International Clone Causes Treatment Failure. Antimicrobial Agents and Chemotherapy 1273–1280
  13. ↑ Unemo (2008) Real-time PCR and subsequent pyrosequencing for screeing of penA mosaic alleles and prediction of reduced susceptibility to expanded-spectrum cephalosorins in Neisseria gonorrhoeae. Acta Pathologica, Microbiologica et Immunologica Scandinavica 116:1001–1008
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