Evolution of Antimicrobial Resistance: Comparison
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Neisseria gonorrhoeae has become a significant global public health problem due to growing infection rates and antibiotic resistance development. In 2012, N. gonorrhoeae positive samples isolated from Southeast Asia were reported to be the first strains showing resistance to all first-line antibiotics. To date, N. gonorrhoeae’s antimicrobial resistance has since been identified against a wide range of antimicrobial drugs globally. Hence, the World Health Organization (WHO) listed N. gonorrhoeae’s drug resistance as high-priority, necessitating novel therapy development. The persistence of N. gonorrhoeae infections globally underlines the need to better understand the molecular basis of N. gonorrhoeae infection, growing antibiotic resistance, and treatment difficulties in underdeveloped countries.

  • Neisseria gonorrhoeae
  • antimicrobial-resistance
  • gonococcal infection
  • drug-resistance

1. Sulphonamides

Sulphonamides were first used to treat N. gonorrhoeae in the 1930s; however, by 1944, 75% of World War II soldiers in the Italian army had experienced treatment failure with these drugs. Sulphonamide antimicrobials compete with the dihydropteroate synthetase (DHPS) enzyme in the production of folic acid[1]. Resistance is established by increasing the production of the standard substrate, p-aminobenzoic acid, or by creating a mutant DHPS with a poor affinity for the antibiotic[2]. In the 1960s, combination therapy with trimethoprim was offered as an alternative to increasing the efficacy of sulphonamide in treating uncomplicated N. gonorrhoeae infections. Trimethoprim prevents susceptible N. gonorrhoeae from converting dihydrofolate to tetrahydrofolate in the metabolic pathway performed by the dihydrofolate reductase (DHFR) enzyme[3]. N. gonorrhoeae DHRF, on the other hand, has a low affinity for trimethoprim and may be genetically changed, making the bacterium less susceptible to this antibiotic[4]. Until the 1970s, the synergic combination of sulphonamides and trimethoprim was utilised to treat gonorrhoeae in high and multi-dose treatment schemes. These drugs inhibit bacterial folic acid synthesis by targeting the bacterial dihydropteroate synthase (DHPS) enzymes[1]. Over synthesis of p-aminobenzoic acid, which dilutes the antimicrobial agent, or changes in the folP gene (point mutations or the presence of a mosaic gene containing DNA sequences from commensal Neisseria spp.), which encodes the drug target DHPS, can cause sulphonamide resistance[5]. The modifications to DHPS result in a significantly reduced affinity for sulphonamide agents as well as bacteriostatic activity[6].

2. Penicillin

Penicillin was introduced as an antibacterial therapy for N. gonorrhoeae in 1943, notably when sulphonamide treatment failed. Penicillin worked by inhibiting the bacterial cell wall production by binding to transpeptidase enzymes in the periplasm of penicillin-binding proteins (PBP). Therefore, penicillin resistance mechanisms in N. gonorrhoeae were linked to reduced sensitivity by cumulative chromosomal changes in various genes associated with cell wall production (penA and penA1) or structures influencing periplasmic drug concentration[1]. However, in the 1960s, penicillin had reduced susceptibility against Neisseria gonorrhoeae. In the 1970s, N. gonorrhoeae isolates had MICs of up to 128 g/mL, thus ending the penicillin era; however, in the 1960s, penicillin had reduced susceptibility against N. gonorrhoeae therapy[7]. The newly discovered resistance mechanism was a plasmid-mediated β-lactamase (bla) gene type TEM (blaTEM), and the isolates were dubbed penicillinase-producing N. gonorrhoeae (PPNG). The plasmids carried by N. gonorrhoeae blaTEM are genetically similar but have various sizes, insertion, or deletion sites and are termed according to their epidemiological origin. The African (5588 bp) is one of the most frequently reported bla-plasmids in N. gonorrhoeae isolates[8].

3. Tetracycline

In the 1950s, tetracycline was offered as a therapeutic alternative for N. gonorrhoeae in individuals allergic to penicillin. Overexpression of penB and mtr in N. gonorrhoeae isolates inhibited tetracycline action, thus establishing an emergence of tetracycline-resistant Neisseria gonorrhoeae [9]. In 1985, the first N. gonorrhoeae isolates with high-level tetracycline resistance (MIC 24–32 g/mL) were isolated; this was said to be a result of the expression of the TetM protein. The emergence of this resistance was the initiation of the quinolone era in N. gonorrhoeae therapy. Tetracyclines limit aminoacyl-tRNA binding to the mRNA-ribosome complex, mostly through binding to the 30S ribosomal subunit, and hence reduce protein synthesis, resulting in a bacteriostatic effect[1][10][1]. Chromosomally-mediated tetracycline resistance in gonococci is caused by mutations that change the structure of the ribosomal protein (target), which interacts with resistance determinants to enhance efflux and reduce the inflow of tetracycline[11].

4. Quinolone

Ciprofloxacin was developed in 1983 and released to the market in the late 1980s. Initially, ciprofloxacin was used to treat N. gonorrhoeae in a single dosage of 250 mg[1]. However, the Centers for Disease Control and Prevention (CDC) initially recommended 500 mg of ciprofloxacin in a single dose treatment. Although isolates with reduced susceptibility (MIC 0.25 g/mL) had been detected before 1989, and despite numerous therapeutic failures reported during the 1990s, ciprofloxacin therapy continued to be used at the exact dosage globally for an additional 10–25 years depending on the country[12]. Quinolones interfere with the activity of DNA gyrase and topoisomerase IV, two topoisomerases that are required for DNA replication, transcription, recombination, and repair[13]. Quinolone antibiotics create a drug–enzyme–DNA complex and then release double-stranded DNA breaks. Resistance to ciprofloxacin in N. gonorrhoeae is mediated by mutations in the quinolone resistance-determining region (QRDR), situated near the topoisomerase’s DNA binding site. Bacterial DNA gyrase and topoisomerase IV are type II topoisomerases that are required for DNA metabolism[12]. They work by breaking and reconnecting double-stranded DNA in an ATP-dependent process. Quinolones provide bactericidal effects via inhibiting DNA gyrase and topoisomerase IV[1].

5. Azithromycin

In the early 1980s, azithromycin was proposed as a potential treatment for Neisseria gonorrhoeae. This macrolide inhibits peptidyl transferase polypeptide chain elongation by interacting with the P site of the 50S ribosomal subunit. Various elements may influence azithromycin activity in Neisseria gonorrhoeae. One of these is the overexpression of the efflux pump mtrCDE, which is guided by the same molecular processes that have been found to reduce N. gonorrhoeae sensitivity to penicillin, raising the azithromycin MIC to 0.5 g/mL[7]. The development of mutations in the L4 ribosomal protein is another cause of azithromycin resistance development. Resistance to azithromycin develops when mutations occur directly in this 23S rRNA domain[14]. Mutations of A2143G or C2599T found in one to four rrl gene alleles encoding the 23S RNA result in azithromycin resistance[15]. In recent years, N. gonorrhoeae with a high level of azithromycin resistance has evolved. The first incidence occurred in 2001, and since then, high-level azithromycin resistance has been detected in many Sub-Saharan countries[3]. By attaching to the 50S ribosomal subunit, macrolides impair protein synthesis by impeding peptidyl-tRNA translocation, blocking the peptide exit channel in 50S subunits by interacting with 23S rRNA, and causing ribosomes to release incomplete polypeptides[1].

6. Ceftriaxone

Previously, ceftriaxone was the drug of choice for N. gonorrhoeae infections. Ceftriaxone aids by binding to PBP2 with great affinity; however, recently, it has been noted that N. gonorrhoeae sensitivity to this antibiotic declined rapidly, and resistance rates have reached 30%. Changes in the penB, mtrR, and penC genes enhance ceftriaxone resistance, and mutations in the penA gene, which encodes PBP2, appear to be the primary ceftriaxone resistance determinant[16]. The changed PBP2 has a lower affinity for ceftriaxone, and resistance to ceftriaxone is characterised by MIC > 0.5 μg/mL by CDC, and most ceftriaxone resistance has been related to the presence of different patterns of PBP2[1]. The rise of ceftriaxone-resistance in N. gonorrhoeae and the lack of a new therapeutic option for N. gonorrhoeae prompted dual therapy regimens using ceftriaxone and azithromycin. Cephalosporins, like other -lactam antibiotics, block peptidoglycan cross-linking inside the bacterial cell wall by binding the -lactam ring to PBPs (transpeptidases), resulting in bactericidal action[17]. Cephalosporin resistance in gonococci is caused mostly by mutations that alter the target proteins (PBPs), but it can also be attributed to increased efflux and decreased inflow of cephalosporin[1].

References

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