Table 2.

Prodrugs and their mechanism of actions.

Prodrugs	Mechanism of Action and Examples
Diazabicyclooctanones (DBOs)	The active drug is produced from DBOs, which are sulfate-containing prodrugs that are in vivo activated by esterase cleavage that intramolecularly assaults the electrophilic neopentyl methylene group [249]. DBOs function as strong inhibitors of class A and class C β-lactamases. The serine active site of the β-lactamase is targeted by an amide group on the five-membered ring of DBOs, forming a carbamoyl adduct. The effectiveness of the antibiotic can be restored by using the prodrug in conjunction with the proper oral β-lactam antibiotics [139,250,251,252]. Examples of DBOs are WCK 5153 (168), ANT3310 (169), and the following: avibactam (170), relebactam (171), nacubactam (172), zidebactam (173) (Figure 17).
β-Lactamase-Activated Ciprofloxacin Prodrug	A prodrug of cephalosporin and fluoroquinolone ((6R,7R) -7-Acetamido-3-(((1-cyclopropyl-6-fluoro-4-oxo-7- (piperazin-1-yl) (piperazin-1-yl) -1,4-dihydroquinoline-3-carbonyl)oxy)- methyl)-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic Acid) created by Evans et al. [253] (174, Figure 17) to deliver ciprofloxacin only to bacteria that express β-lactamase. When cephalosporin is cleaved by β-lactamase, the prodrug’s 3′-cephem ester, which was created by attaching ciprofloxacin via a carboxylic acid, releases ciprofloxacin.
Azithromycin Prodrug CSY5669	Both an antibiotic and an immunomodulator, azithromycin. Azithromycin prodrug (CSY5669) (175, Figure 17) was created by Saris et al. [254] to enhance the immunomodulatory properties of azithromycin by combining it with nitric oxide and acetate as immune activators. It is possible to use CSY5669 as an adjuvant drug in the treatment of pneumonia brought on by MRSA by assisting in the eradication of bacteria and limiting inflammation-associated pathology. The prodrug showed an enhancement of intracellular killing of MARSA in monocyte-derived macrophages and peripheral blood leukocytes as well as reduced inflammatory responses in mice airways in vivo.
Tedizolid phosphate (TR701)	Prodrug of the antibiotic oxazolidinone tedizolid (TR701) (176, Figure 17), which is used to treat bacterial skin infections. Plasma phosphatasese converts it to its active parent drug tidezolide, which is highly active in vitro against Gram-positive bacteria, including MRSA [255,256,257].
Pretomanid	A prodrug of an antibiotic (177, Figure 17) that, after being converted to a desnitro derivative by Mycobacterium tuberculosis deazaflavin-dependent nitroreductase (Ddn) [258], acts by raising nitric oxide levels. To treat tuberculosis with drug resistance, it is used with bedaquiline and linezolid [259].
Ceftaroline fosamil	A prodrug (178, Figure 17) that is activated by plasma phosphatase to produce ceftaroline, which is used to treat community-acquired bacterial pneumonia (CABP) and acute bacterial skin infections [260,261].
Cephalosporin-3′-diazeniumdiolates (C3Ds) prodrugs	After reacting with β-lactamases and being broken down by transpeptidases, a nitric oxide (NO) donor prodrug with a β-lactam ring in its structure selectively releases NO. The diazeniumdiolate NO donor-containing PYRRO-C3D (179, Figure 17) is one of two C3Ds that are currently being developed. The second prodrug is DEA-C3D (180, Figure 17) which contains the phenacetyl side chain of cefaloram and the diazeniumdiolate NO donor. The prodrugs are a good possibility for lowering antibiotic tolerance linked to biofilms [262,263,264].
Triclosan glycoside prodrugs	The identification of the bacterial enzyme glycosidase resulted in the identification of glycoside derivatives as bacterium-targeting prodrugs (181, Figure 17). Gram-positive and Gram-negative bacteria are inhibited by triclosan glycoside derivatives (α-D-glycopyranosides and β-D-glycopyranosides), which has the potential to be utilized orally for the treatment of systemic infections [265,266,267]
5-Modified 2ʹ-Deoxyuridines prodrugs	The precise mechanism by which pyrimidine nucleoside derivatives work is unknown; however, some of the compounds inhibited the microbial enzyme flavin-dependent thymidylate synthase (ThyX), which is not present in humans, and others operated on mycobacterial cell wall destruction [268]. Negrya et al. [269] created carrier-linked prodrugs of 5-modified 2’-deoxyuridines (182, Figure 17) since the parent drugs, 5-dodecyloxymethyl 2’-deoxyuridine and 5- [4-decyl-(1,2,3-triazol-1-yl) methyl]-2’-deoxyuridine, were poorly soluble in water. To increase solubility, a triethylene and tetraethylene glycol moiety was linked to the 3′ and 5′ hydroxyl groups of the parent molecules using a carbonate group.
Tebipenem pivoxil Prodrug	Tebipenem pivoxil HBr salt (183, Figure 17) is a tebipenem ester prodrug that can be taken orally and has improved bioavailability. It is now being developed to treat difficult urinary tract infections in adults. It is approved for use in Japan to treat ear, nose, throat, and respiratory infections in children [270].
FtsZ-Targeting Benzamide Prodrugs	A prokaryote-specific protein called Fts-Z (Filamenting temperature-sensitive mutant Z) is involved in bacterial cell division. In order to combat methicillin-sensitive and resistant Staphylococcus aureus (MSSA and MRSA), PC190723 is a FtsZ-Targeting Benzamide the N-Mannich base prodrug TXY436 (184, Figure 17) was developed as a result of poor solubility; it has improved pharmacological characteristics but requires high effective doses. Because of this, a novel prodrug called TXA709 (185, Figure 17) was developed based on TXY436 with a CF3 group in place of the Cl on the pyridyl ring, giving it a longer half-life and higher oral bioavailability than TXY436 [271,272].
Carvacrol Prodrugs	A naturally occurring monoterpene called carvacrol can damage bacterial membranes and prevent Gram-positive bacteria from forming biofilms [273]. Carvacrol prodrugs (WSCP18-19) (186, Figure 17) were created by prenylating the hydroxyl group of carvacrol due to its low water solubility and chemical stability. The prodrugs exhibit good plasma stability, minimal toxicity, and a potential antibacterial action against S. aureus and S. epidermidis [274].
ADC111, ADC112 and ADC113	Fleck et al. [275] examined thousands of chimicals in order to find non-specific molecules that prevent alamarBlue, a viability dye, from being reduced. Three prodrugs— ADC111, an analog of the nitrofuran prodrug (187), ADC112, an analog of the tilbroquinol antimicrobial (188), and ADC113, a molecule with a di-ketone functionality that is not a member of any class of recognized antimicrobials (189)—are available (Figure 17). The prodrugs have demonstrated that they are effective in killing E. coli cells [276,277].
Contezolid acefosamil (CZA) prodrug	A brand-new oral oxazolidinone antibacterial medication called Contezolid (CZD) is effective against the majority of aerobic Gram-positive bacteria, including MRSA and vancomycin-resistant Enterococcus. The medication prevents the synthesis of 70S initiation complex, which is essential for bacterial reproduction [278]. As a result of its low solubility, the drug’s intravenous (IV) administration is restricted. Giving patients with diabetic foot infections more therapeutic options in hospitals and outpatient settings is therapy with IV administration followed by oral CZD [279]. Liu et al. [280] created the contezolid acefosamil (CZA) prodrug (190, Figure 17), an isoxazol-3-yl phosphoramidate derivative with excellent water solubility and good stability in pH conditions suited for IV delivery.