Acinetobacter baumannii is a Gram-negative, non-fermentative, and oxidase-negative causative agent found in the general environment, particularly in hospital settings. It is in the role of starting opportunistic illnesses like meningitis, pneumonia, urinary and respiratory tract infections, patient sepsis in critical care units (ICU), and burn infections. [1 – 4]. Bacteremia occurs in 25% to 30% of cases due to toxic shock and is typically linked to widespread intravascular coagulation. While this pathogen may briefly establish itself [5], it often leads to invasive infection, particularly in individuals with burn injuries. Hospital results are linked to a mortality rate of 23%, which increases to 43% when patients reach the Intensive Care Unit (ICU) [7].

Acinetobacter isolates are now frequently multi-drug resistant. Reportedly, over 80% of isolates are now aminoglycoside-resistant and the resistance to quinolones is also on the rise which consequently has resulted in expanded therapeutic problems and concerns [8]. These resistances could be due to either inherent or acquired mechanisms [9]. Quinolone resistance is mediated by several mechanisms, including altered expression of efflux pumps. A. baumannii efflux pump is AdeABC and this means the setting likely has a substantial contributory role in resistance genesis [10]. The development of resistance is one of the various mechanisms those leads to antibiotic resistance and these mechanisms should be blocked or disrupted. Efflux pump inhibition involves several strategies, all aiming to act by direct interference with the enzymatic process that uses energy for drug export: disarming (‘discontinuing’) efflux pumps, coupling or obstructing the efflux site and not allowing for the formation and assembly of functional apparatus. 

PAβN blocks the efflux pump and participates in a competitive interaction with antibiotics, although the mechanism of action of 1-(1-naphtylmethyl)-piperazine (NMP) inhibitor remains unknown. The resistance of A. baumannii isolates to ciprofloxacin was assessed in both the presence and absence of efflux pump inhibitors [11-14].

The inclusion of quinolone resistance (qnr) genes on the plasmid confers a modest amount of resistance to quinolones, therefore establishing an associated mechanism that enhances resistance. The proteins in issue have a poor distribution rate, and most of the studies have been conducted on the bacteria of the Enterobacteriaceae family. Investigations attempting to identify the qnr genes in A. baumannii isolates have not yielded substantial findings [15]. Genetic alterations in quinolone resistance-determining regions (QRDR) promote the development of quinolone resistance by particularly affecting the target enzymes of DNA gyrase (gyrA) and Topoisomerase IV (parC). Quinolones have a significant effect on some enzymes, such DNA gyrase, which they block by attaching specifically to the gene encoding for the enzyme and causing a mutation [16]. The objective of the current study was to investigate several mechanisms of resistance to fluoroquinolones, including the efflux pump, qnr genes or mutation, and decrease of resistance by efflux pump inhibition utilizing two compounds of PAβN and NMP. The necessity of growing Acinetobacter resistance to the majority of antibiotics and the importance of fluoroquinolones in the treatment of infections brought on by these isolates served as the driving forces for this inquiry.

The broad spectrum of activity of fluoroquinolones, which are synthetic antibacterial agents, is well established. They have high efficacy against a broad spectrum of both gram-negative and gram-positive pathogenic microorganisms. During recent years, the worldwide resistance to fluoroquinolones has increased due to their extensive usage [18]. Mutagens in the quinolone resistance-determining areas of genes encoding gyrase and topoisomerase [19] describe the resistance mechanism to fluoroquinolones.  Another well recognized mechanism of fluoroquinolone resistance is the reduction of drug accumulation inside cells by the activation of efflux pumps or the downregulation of outer membrane porin expression [20]. Reports of plasmid-mediated quinolone resistance (PMQR) have been documented since 1998. These are capable of being transferred horizontally and are commonly known as "PMQR." The three PMQR genes consist of the qnr gene, the aac(6′)-Ib-cr gene (aminoglycoside acetyltransferase function), and the oqxAB and qepA genes (efflux pumps). [21]

The proteins encoded by the plasmid qnr genes (qnrA, qnrB, and qnrS) are members of the pentapeptide repeat family. These proteins confer intravenous protection to DNA gyrase and topoisomerase against inhibition caused by fluoroquinolones. The aac(6′)-Ib-cr is a dual-functional aminoglycoside acetyltransferase involved in modifying the pH of fluoroquinolones, such as ciprofloxacin and norfloxacin, which have an amino nitrogen on the C7 of the piperazinyl ring, thereby reducing their efficacy [22]. Fluoroquinolones that do not have an unsubstituted piperazinyl nitrogen are unaffected [23]. The plasmid-mediated qepA efflux pump is a member of the major facilitator superfamily, which greatly reduces the vulnerability to hydrophilic fluoroquinolones, particularly ciprofloxacin [24]. It is a multidrug efflux pump encoded by the oqxAB gene, which belongs to the resistance nodulation division family[25].

The non-fermenting gram negative bacteria Acinetobacter baumannii and Pseudomonas aeruginosa are widely acknowledged as causative agents of healthcare acquired illnesses. Resistance to fluoroquinolones has been found to be a significant issue in both species, mostly because of their rapid acquisition of resistance determinants [19]. The majority of research focused on the occurrence of PMQR genes in Enterobacteriaceae [26–28]. The available data about the frequency of PMQR genes in clinical isolates of Pseudomonas aeruginosa and Acinetobacter baumannii is limited [29].

When fluoroquinolones resistance genes are found on a plasmid, they can spread horizontally by gene transfer to several bacterial species. Monitoring the propagation of resistant plasmids is made possible by the identification of comparable plasmids linked to specific resistance genes. As a result, PBRT, or polymerase chain reaction-based replicon typing, has become the global standard for plasmid identification and typing [30].

The bactericidal properties of quinolones are attributed to their wide range of activity and their distinctive bicyclic core structure, which closely resembles that of 4-quinolone. Quinolone antibiotics are mostly fluoroquinolones that exhibit effectiveness against agents of both Gram-negative and Gram-positive bacteria [31]. With respect to its mode of action, quinolone antibiotics disrupt DNA replication by preventing bacterial DNA from becoming loose and being replicated. The mechanism of action of quinolones involves the inhibition of ligase activity expressed by type II topoisomerases, including DNA gyrase and topoisomerase IV. These enzymes often produce supercoiling in conjunction with DNA nucleases. The disruption of ligase function results in the persistence of double-stranded DNA breaks in bacteria, ultimately leading to cell death. Significantly, quinolones mostly impact the activity of gyrase, but their toxicity against topoisomerase IV is secondary. This means that there is no evidence of independent parC mutations without corresponding changes in gyrA.

Three distinct mechanisms contribute to quinolone resistance: (i) target mutations in gyrase and topoisomerase IV, which reduce the interactions between quinolones and enzymes; (ii) plasmid-borne resistance facilitated by nr proteins, the AMEs AAC(60)-Ib-cr and AAC(60)-Ib-cr5, and plasmid-encoded efflux pumps; and (iii) chromosome-derived resistance caused by either low expression of porins or overexpression of chromosome-encoded efflux pumps [31-33]. An updated analysis revealed that A. baumannii exhibited resistance to fluoroquinolones in 50% to 73% of cases. In underdeveloped nations, the resistance to fluoroquinolones has significantly increased in recent years, reaching 75% to 97.7% [34]. Table 1 presents a comprehensive compilation of documented resistance mechanisms to quinolones in A. baumannii.

Table (1). Quinolone-specific mechanisms of A. baumannii resistance.

CIP = ciprofloxacin; LEV = levofloxacin; NOR = norfloxacin; * = resistance to CIP, LEV, NOR, and enrofloxacin in the presence of rmtB [47].

Chronic and widespread quinolone resistance resulting from hyperactive RND pumps has been well-documented [35]. Genetic variations in the TCS elements, namely in the regulator (AdeR) with polymorphisms D20N, A91V, A136V, and P116L, and the sensor (AdeS) with polymorphisms G30D, A94V, G103D, G186V, and T153M, of the AdeABC pump, lead to increased efflux of ciprofloxacin. Genetic mutations in the adeR and adeS genes appear to stimulate the excessive production of the AdeABC efflux system, particularly the adeB gene component. These mutations are linked to the development of resistance to ciprofloxacin, norfloxacin, and ofloxacin. Furthermore, A. baumannii employs efflux systems AdeIJK and AdeFGH in addition to AdeABC to eliminate fluoroquinolones from the cell, leading to elevated minimum inhibitory concentrations (MICs). 

Furthermore, the role of the multidrug and toxic compound extrusion (MATE) transporters AbeM and AbeS in A. baumannii resistance to quinolones is a subject of debate. The primary target of AbeM pump is the hydrophilic fluoroquinolones, namely norfloxacin and ciprofloxacin, rather than the hydrophobic ones which include ofloxacin. Generally, these non-ring-disrupting enzyme (RDD) efflux pumps provide a modest amount of resistance to fluoroquinolones, despite some research indicating otherwise [36]. Quinolone resistance-determining regions (QRDRs) mostly pertain to modifications in target locations inside gyrase, such as mutations in Ser83Leu, Gly81Asp, and Ser81Leu that hinder the binding of quinolones to its alpha-subunit. Similarly, QRDRs also include mutations in Ser80Leu, Glu84Lys, Gly78Cys, and Ser84Leu in the subunit C of topoisomerase IV enzyme. While an individual point mutation in DNA gyrase is typically insufficient to confer resistance to fluoroquinolones in A. baumannii (perhaps only against levofloxacin; single parC mutations are associated with ciprofloxacin resistance), simultaneous mutations in QRDR regions of the gyrA and parC genes are associated with a substantial increase in quinolone resistance [37,38]. Minor relevance is attributed to alterations in the gyrB and parE genes. Plasmid-mediated quinolone resistance (PMQR) has been recently recognized as a clinical challenge in the context of A. baumannii infections. However, it often results in a very modest degree of (6-10 fold) resistance [39].

The Qnr genes qnrAI, qnrB, qnrB19, and qnrS encode pentapeptide-repeat protein family members, which are homologous to McbG and MfpA proteins. These proteins initially inhibit gyrase activity by competing with DNA for binding, resulting in reduced DNA binding with topoisomerase. This protection of enzyme-DNA complexes from quinolones is achieved by this mechanism [40].

A consequence of the DNA homology described earlier, these pentapeptide repeat-containing Qnr proteins can also bind to gyrase and topoisomerase IV, hence inhibiting the cleavage of quinolones. This ultimately results in the aggregation and accumulation of double-stranded DNA breaks, which would be fatal to A. baumannii [41]. PMQR caused by AMEs AAC(60)-Ib-cr and AAC(60)-Ib-cr5 is primarily caused by mutant alleles of the 6’ aminoglycoside acetyltransferase-Ib gene ("-cr" indicating resistance to ciprofloxacin; W102R and D179Y mutations). These mutant alleles encode enzymes that acetylate the C7 unsubstituted nitrogen in the piperazine ring of norfloxacin and ciprofloxacin. The third classification of plasmid-borne quinolone resistance pertains to efflux pumps. However, there is currently no recorded instance of such resistance in A. baumannii. QepA and OqxAB are the first identified quinolone efflux pumps known to contribute to resistance to norfloxacin, enrofloxacin, levofloxacin, and ciprofloxacin in rmtB-positive E. Coli.

Resistance to fluoroquinolones originating from the chromosome is linked to either a reduced influx rhythm caused by downregulated or malfunctioning porins, or to hyperactive efflux membrane pumps. Porins are virulence proteins associated with Gram-negative bacteria that control cellular permeability via the outer membrane. They are specifically associated with carbapenem resistance, as seen in Pseudomonas aeruginosa isolates with reduced OprD expression. Porin genes such as ompA, omp25, omp33, oprC, oprD, oprW, dcap-like, and carO have been associated with this mechanism of resistance. Although resistance to quinolones has not been shown, there appears to be a correlation between low relative expression of Omp25 and CarO porins and resistant A. baumannii strains [11,35].  Chromosomal-encoded efflux pumps and porin modifications alone do not appear to provide substantial clinical resistance to A. baumannii in the context of fluoroquinolones [31,36].

 As previously explained, A. baumannii can develop antibiotic resistance through many mechanisms: by modifying the structure of the drug target, by regulating the movement of antibiotics across its membranes, and by enzymatically modifying antibiotics to make them ineffective. Secondary to innate mechanisms of antibiotic resistance that are de facto conferred by genes, A. baumannii may facilitate antibiotic resistance through various mechanisms linked with its virulence: outer membrane proteins (like porins), cell envelope factors (like LPS and the capsule around its bacterial surface), specific enzymes (like phospholipases C and D, and glycan-specific adamalysin-like protease CpaA), quorum sensing, and biofilm formation (BfmRS TCS regulating Csu pili, Csu expression regulated by the GacSA TCS, biofilm-associated proteins BapAb, synthesis of the exopolysaccharide polyβ-1,6-N-acetylglucosamine PNAG, acyl-homoserine lactones through AbaR receptor, and AbaI autoinducer synthase), by attaining twitching motility via type IV pili, micronutrient acquisition systems (like siderophores and iron transporters FecA and FecI, ZnuABC transporter, and ZigA GTPase incorporating a zinc-scavenging system, resistance-associated macrophage protein NRAMP for manganese transportation), type II (with CpaA and lipases LipA and LipH as effectors), and type VI protein secretion systems [43]. Application of next-generation sequencing methods has enabled doctors to unravel the molecular processes of antibiotic resistance in PDR isolates of A. baumannii, and whole genome sequencing (WGS) has become a potent weapon in the clinician's arsenal. The future application of whole genome sequencing (WGS) and other next-generation sequencing (NGS) methods in diagnosis might offer valuable insights on the microbiological behavior and virulence of individual cases of severe A. baumannii infection. In addition to prompt diagnosis, thorough characterisation of the genetic composition of each isolate might offer valuable insights into antibiotic therapy (in the context of precision medicine) and the discovery of new therapeutic targets [44,45].

Acknowledgments :

We would like to thank everyone who helped us complete this work, especially the Biostatistics Unit at Al-Najaf Teaching Hospital and the Medical Microbiology, Medicines and Therapeutics Branches at the College of Medicine.

The authors declare that they have no conflict of interest

No funding sources

The study was approved by the Jabir ibn hayyan University of Medical and Pharmaceutical Sciences.

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