Table 1.

Examples of PMPs as key drug targets. The examples of pathogenic organisms in which the protein exists, the effect of the corresponding disease on human health, the currently available drug targets, and the homologues among different domains are described for type-II NADH dehydrogenase [24,25,26,27,28,29], periplasmic nitrate reductase [30,31,32,33], CymA, alkaline phosphatase [34,35], ecto-5′-nucleotidase [36,37], acetylcholine esterase [38,39], alternative oxidase [40,41], cytochrome c [42,43], and dihydroorotate dehydrogenase [42,44].

Example Protein (Model Organism)	Examples of Pathogenic Organism(s)	Effect on Human Health	Current Available Drugs/Treatments	Homologues among Domains/Species
Type-II NADH dehydrogenase (NDH-2) (Caldalkalibacillus thermarum)	Mycobacterium tuberculosis	Tuberculosis; 1.4M deaths worldwide in 2019 [24].	Bedaquiline (against M. tuberculosis)NDH-2 targeting thioquinazoline (TQZ)-based and tetrahydroindazole (THI)-based inhibitor candidates [25].	Not reported in mammalian biology; is in prokaryotes and yeast.
	Staphylococcus aureus	Opportunistic and nosocomial infections, 50,000 deaths/year in the USA [26].
	Escherichia coli	Gastrointestinal infections causing an estimated 325,000 deaths in developing countries [27]. Cause of 90% of urinary tract infections, 135M cases/year [28]. Horizontal gene transfer of antibiotic resistance to other species [29].
Periplasmic nitrate reductase (Nap) (Cupriavidus necator, Rhodobacter sphaeroides)	Haemophilus influenzae	Respiratory disease; 199,000 deaths of children/year in 2008 [30].	Not reported targeting Nap. Cefotaxime 80% effective against extensive drug resistant (XDR) strains [31].	Reported in prokaryotes (specifically in bacteria) and eukaryotes; also, in humans.
	Pseudomonas aeruginosa	Sixth most common nosocomial pathogen in the USA [32]. Lung infection; 2700 deaths/year in the USA [33].	Not reported targeting Nap. Against multi-drug-resistant strains, cefiderocol and imipenem-cilastatin/relebactam in phase II clinical trials [32].
CymA	Shewanella putrificans Shewanella alga	Food spoilage, necrosis, seafood toxin producing (opportunistic pathogen).	N/A	Reported in prokaryotes (specifically in bacteria). Not reported in mammalian biology.
Alkaline phosphatase (AP) (Homo sapiens)	Causes disease in humans	Hydroxyapatite deposition disease (HADD) [34].	Paracetamol and/or nonsteroidal anti-inflammatory drugs, barbotage, and steroid injections for severe cases [35].	Reported in prokaryotes (specifically in bacteria) and eukaryotes; also, in humans.
Ecto-5′-nucleotidase (CD73) (Homo sapiens)	N/A	Tumor progression; 47,050 deaths/year in the USA in 2020 [36].	Monoclonal antibodies: CPI-006, CPI-444, oleclumab, TJ004309, NZV930, and BMS-986179 [37].	Reported in prokaryotes (specifically in bacteria) and eukaryotes; also, in humans.
Acetylcholine esterase (Homo sapiens)	Causes disease in humans	Senile plaque formation (Alzheimer’s disease); 122,019 deaths/year in the USA in 2018 [38].	Donepezil, rivastigmine (Exelon) and galantamine (Razadyne, Nivalin) [39].	Reported in prokaryotes (specifically in bacteria) and eukaryotes; also, in humans.
Alternative oxidase (AO) (Trypanosoma brucei)	Trypanosoma brucei	African trypanosomiasis (sleeping sickness); 116 deaths in 2019 [40].	Pentamidine (early stage), nifurtimox and eflornithine (late stage) for T. brucei gambiense; Suramin (early stage) and melarsoprol (late stage) for T. brucei rhodesiense [41].	Reported in prokaryotes (specifically in bacteria) and eukaryotes. Not reported in mammalian biology.
Cytochrome c	N/A	Inhibits cancer progression;9,900,000 total cancer deaths/year [42].	Cisplatin [43].	Reported in prokaryotes (specifically in bacteria) and eukaryotes; also, in humans.
Dihydroorotate dehydrogenase (DHODH) (Homo sapiens)	N/A	Inhibits cancer progression; 9,900,000 total cancer deaths/year [42].	Brequinar and leflunomide [44].	Reported in prokaryotes (specifically in bacteria) and eukaryotes; also, in humans.